Diazepinone derivatives and their use in the treatment of hepatitis b infections

ABSTRACT

Provided herein are compounds of formula (I) and (V) useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.

RELATED APPLICATIONS

This application claims benefit of U.S. provisional patent applicationNo. 62/356,489, filed Jun. 29, 2016; and U.S. provisional patentapplication No. 62/511,573, filed May 26, 2017; the entire contents ofeach of which are incorporated herein by reference.

BACKGROUND

Chronic hepatitis B virus (HBV) infection is a significant global healthproblem, affecting over 5% of the world population (over 350 millionpeople worldwide and 1.25 million individuals in the U.S.).

Despite the availability of a prophylactic HBV vaccine, the burden ofchronic HBV infection continues to be a significant unmet worldwidemedical problem, due to suboptimal treatment options and sustained ratesof new infections in most parts of the developing world. Currenttreatments do not provide a cure and are limited to only two classes ofagents (interferon alpha and nucleoside analogues/inhibitors of theviral polymerase); drug resistance, low efficacy, and tolerabilityissues limit their impact. The low cure rates of HBV are attributed atleast in part to the fact that complete suppression of virus productionis difficult to achieve with a single antiviral agent. However,persistent suppression of HBV DNA slows liver disease progression andhelps to prevent hepatocellular carcinoma. Current therapy goals forHBV-infected patients are directed to reducing serum HBV DNA to low orundetectable levels, and to ultimately reducing or preventing thedevelopment of cirrhosis and hepatocellular carcinoma.

The HBV capsid protein plays essential functions during the viral lifecycle. HBV capsid/core proteins form metastable viral particles orprotein shells that protect the viral genome during intercellularpassage, and also play a central role in viral replication processes,including genome encapsidation, genome replication, and virionmorphogenesis and egress. Capsid structures also respond toenvironmental cues to allow un-coating after viral entry. Consistently,the appropriate timing of capsid assembly and dis-assembly, theappropriate capsid stability and the function of core protein have beenfound to be critical for viral infectivity.

There is a need in the art for therapeutic agents that can increase thesuppression of virus production and that can treat, ameliorate, orprevent HBV infection. Administration of such therapeutic agents to anHBV infected patient, either as monotherapy or in combination with otherHBV treatments or ancillary treatments, will lead to significantlyreduced virus burden, improved prognosis, diminished progression of thedisease and enhanced seroconversion rates.

SUMMARY

Provided herein are compounds useful for the treatment of HBV infectionin a subject in need thereof.

Thus, in an aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

A is CH₂ or C═O;

R¹ is H, C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-alkyl-OH, or C₁-C₆-haloalkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹,C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl,alkylene, cycloalkyl, and heterocycloalkyl are optionally substitutedwith 1, 2, or 3 groups, each independently selected from —OH and halo;or

two R² groups together form a C₃-C₆ spiro cycloalkyl, wherein thecyloalkyl is optionally substituted with 1, 2, or 3 groups, eachindividually selected from —OH and halo;

R³ is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl,(CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and(CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁵ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, andC₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is, at each occurrence, independently selected from H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C(O) C₁-C₆-alkyl and C₁-C₆-alkyl-OH;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

R^(a) is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is, at each occurrence, independently selected from H andC₁-C₆-alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4;

q is 0 or 1; and

a

line denotes an optionally double bond.

In an embodiment, provided herein is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein

A is CH₂ or C═O;

R¹ is H, C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-alkyl-OH, or C₁-C₆-haloalkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹,C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,or 3 groups, each independently selected from —OH and halo;

R³ is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl,(CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and(CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁵ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, andC₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is, at each occurrence, independently selected from H, C₁-C₆-alkyl,and C₁-C₆-alkyl-OH;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

R^(a) is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is, at each occurrence, independently selected from H andC₁-C₆-alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4;

q is 0 or 1; and

a

line denotes an optionally double bond.

In an embodiment, the compound of Formula I has the structure of FormulaII:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I or Formula II has thestructure of Formula III:

or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein

A is CH₂ or C═O;

R¹ is H, C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-alkyl-OH, or C₁-C₆-haloalkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹,C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl,alkylene, cycloalkyl, and heterocycloalkyl are optionally substitutedwith 1, 2, or 3 groups, each independently selected from —OH and halo;or

two R² groups together form a C₃-C₆ spiro cycloalkyl, wherein thecyloalkyl is optionally substituted with 1, 2, or 3 groups, eachindividually selected from —OH and halo;

R³ is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl,(CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and(CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁵ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, andC₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is, at each occurrence, independently selected from H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C(O) C₁-C₆-alkyl and C₁-C₆-alkyl-OH;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

R^(a) is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is, at each occurrence, independently selected from H andC₁-C₆-alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4; and

a

line denotes an optionally double bond.

In another aspect, provided herein is a pharmaceutical compositioncomprising a compound of Formula I, II, III, IV, or V, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier.

In another aspect, provided herein is a pharmaceutical compositioncomprising a disclosed compound and a pharmaceutically acceptablecarrier.

In another aspect, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula I, II, III, IV, or V, or a pharmaceutically acceptable saltthereof.

In another aspect, provided herein is a method of inhibiting or reducingthe formation or presence of HBV DNA-containing particles or HBVRNA-containing particles in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of Formula, I, II, III, IV, or V, or a pharmaceuticallyacceptable salt thereof.

In an embodiment, any of the methods provided herein can furthercomprising administering to the individual at least one additionaltherapeutic agent selected from the group consisting of an HBVpolymerase inhibitor, immunomodulatory agents, interferon, viral entryinhibitor, viral maturation inhibitor, capsid assembly modulator,reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, aTLR-agonist, an HBV vaccine, and any combination thereof.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the X-ray crystal structure of the di p-nitro-benzoic acidanalogue of Intermediate 16, also referred to as compound 151.

DETAILED DESCRIPTION

Provided herein are compounds, e.g., the compounds of Formulas I, II,III, IV, or V, or pharmaceutically acceptable salts thereof, that areuseful in the treatment and prevention of HBV infection in subject.

Without being bound to any particular mechanism of action, thesecompounds are believed to modulate or disrupt HBV assembly and other HBVcore protein functions necessary for HBV replication or the generationof infectious particles. In addition, or alternatively, the compoundsmay disrupt HBV capsid assembly to induce production of defective viralparticles with greatly reduced infectivity or replication capacity. Inother words, the compounds provided herein may act as capsid assemblymodulators by modulating (e.g., accelerating, delaying, inhibiting,disrupting or reducing) normal viral capsid assembly or disassembly,binding capsids, and/or altering metabolism of cellular polyproteins andprecursors. The modulation may occur when the capsid protein is mature,or during viral infectivity. The disclosed compounds can be used inmethods of modulating the activity or properties of HBV cccDNA, or thegeneration or release of HBV RNA particles from within an infected cell.

In one embodiment, the compounds described herein are suitable formonotherapy and are effective against natural or native HBV strains andagainst HBV strains resistant to currently known drugs. In anotherembodiment, the compounds described herein are suitable for use incombination therapy.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in cellculture, molecular genetics, organic chemistry, and peptide chemistryare those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more thanone (i.e. to at least one) of the grammatical object of the article. Byway of example, “an element” means one element or more than one element.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent on the context inwhich it is used. As used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, the term “about”is meant to encompass variations of 20% or 100%, including 5%, 1%, and0.1% from the specified value, as such variations are appropriate toperform the disclosed methods.

As used herein, the term “capsid assembly modulator” refers to acompound that disrupts or accelerates or inhibits or hinders or delaysor reduces or modifies normal capsid assembly (e.g., during maturation)or normal capsid disassembly (e.g., during infectivity) or perturbscapsid stability, thereby inducing aberrant capsid morphology andfunction. In one embodiment, a capsid assembly modulator acceleratescapsid assembly or disassembly, thereby inducing aberrant capsidmorphology. In another embodiment, a capsid assembly modulator interacts(e.g. binds at an active site, binds at an allosteric site, modifies orhinders folding and the like) with the major capsid assembly protein(CA), thereby disrupting capsid assembly or disassembly. In yet anotherembodiment, a capsid assembly modulator causes a perturbation instructure or function of CA (e.g., ability of CA to assemble,disassemble, bind to a substrate, fold into a suitable conformation, orthe like), which attenuates viral infectivity or is lethal to the virus.

As used herein, the term “treatment” or “treating” is defined as theapplication or administration of a therapeutic agent, i.e., a disclosedcompound (alone or in combination with another pharmaceutical agent), toa patient, or application or administration of a therapeutic agent to anisolated tissue or cell line from a patient (e.g., for diagnosis or exvivo applications), who has an HBV infection, a symptom of HBV infectionor the potential to develop an HBV infection, with the purpose to cure,heal, alleviate, relieve, alter, remedy, ameliorate, improve or affectthe HBV infection, the symptoms of HBV infection, or the potential todevelop an HBV infection. Such treatments may be specifically tailoredor modified, based on knowledge obtained from the field ofpharmacogenomics.

As used herein, the term “prevent” or “prevention” means no disorder ordisease development if none had occurred, or no further disorder ordisease development if there had already been development of thedisorder or disease. Also considered is the ability of one to preventsome or all of the symptoms associated with the disorder or disease.

As used herein, the term “patient,” “individual” or “subject” refers toa human or a non-human mammal. Non-human mammals include, for example,livestock and pets, such as ovine, bovine, porcine, canine, feline andmurine mammals. Preferably, the patient, subject, or individual ishuman.

As used herein, the terms “effective amount,” “pharmaceuticallyeffective amount,” and “therapeutically effective amount” refer to anontoxic but sufficient amount of an agent to provide the desiredbiological result. That result may be reduction or alleviation of thesigns, symptoms, or causes of a disease, or any other desired alterationof a biological system. An appropriate therapeutic amount in anyindividual case may be determined by one of ordinary skill in the artusing routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynon-toxic, i.e., the material may be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent invention include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

As used herein, the term “composition” or “pharmaceutical composition”refers to a mixture of at least one compound useful within the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a patient orsubject. Multiple techniques of administering a compound exist in theart including, but not limited to, intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary, and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound useful within theinvention within or to the patient such that it may perform its intendedfunction. Typically, such constructs are carried or transported from oneorgan, or portion of the body, to another organ, or portion of the body.

Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation, including the compound usefulwithin the invention, and not injurious to the patient. Some examples ofmaterials that may serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; surface active agents; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffersolutions; and other non-toxic compatible substances employed inpharmaceutical formulations.

As used herein, “pharmaceutically acceptable carrier” also includes anyand all coatings, antibacterial and antifungal agents, and absorptiondelaying agents, and the like that are compatible with the activity ofthe compound useful within the invention, and are physiologicallyacceptable to the patient. Supplementary active compounds may also beincorporated into the compositions. The “pharmaceutically acceptablecarrier” may further include a pharmaceutically acceptable salt of thecompound useful within the invention. Other additional ingredients thatmay be included in the pharmaceutical compositions used in the practiceof the invention are known in the art and described, for example inRemington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co.,1985, Easton, Pa.), which is incorporated herein by reference.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e.,C₀-C₆-alkyl means null or an alkyl having one to six carbon atoms) andincludes straight and branched chains. Examples include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, andhexyl. Other examples of C₁-C₆-alkyl include ethyl, methyl, isopropyl,isobutyl, n-pentyl, and n-hexyl.

As used herein, the term “alkenyl,” denotes a monovalent group derivedfrom a hydrocarbon moiety containing at least two carbon atoms and atleast one carbon-carbon double bond. The double bond may or may not bethe point of attachment to another group. Alkenyl groups (e.g.,C₂-C₈-alkenyl) include, but are not limited to, for example, ethenyl,propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl,octenyl and the like.

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent means, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine,more preferably, fluorine or chlorine.

As used herein, the term “haloalkyl” refers to alkyl radicals whereinany one or more of the alkyl carbon atoms is substituted with halo asdefined above. Haloalkyl embraces monohaloalkyl, dihaloalkyl, andpolyhaloalkyl radicals. The term “haloalkyl” includes, but is notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, and pentafluoroethyl.

As used herein, the term “cycloalkyl” refers to a mono cyclic orpolycyclic non-aromatic radical, wherein each of the atoms forming thering (i.e., skeletal atoms) is a carbon atom. In one embodiment, thecycloalkyl group is saturated or partially unsaturated. In anotherembodiment, the cycloalkyl group is fused with an aromatic ring.Cycloalkyl groups include groups having 3 to 10 ring atoms(C₃-C₁₀-cycloalkyl), groups having 3 to 8 ring atoms (C₃-C₆-cycloalkyl),groups having 3 to 7 ring atoms (C₃-C₇-cycloalkyl), and groups having 3to 6 ring atoms (C₃-C₆-cycloalkyl). Monocyclic cycloalkyls include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Dicyclic cycloalkyls include, but are notlimited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene.Polycyclic cycloalkyls include adamantine and norbornane. The termcycloalkyl includes unsaturated nonaromatic cyclic groups, which containat least one carbon carbon double bond or one carbon carbon triple bond.

As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers toa heteroalicyclic group containing one to four ring heteroatoms eachselected from O, S, and N. In one embodiment, each heterocyclyl grouphas from 3 to 10 atoms in its ring system, with the proviso that thering of said group does not contain two adjacent O or S atoms.Heterocyclyl substituents may be alternatively defined by the number ofcarbon atoms, e.g., C₂-C₈-heterocyclyl indicates the number of carbonatoms contained in the heterocyclic group without including the numberof heteroatoms. For example, a C₂-C₈-heterocyclyl will include anadditional one to four heteroatoms. Preferably, the heterocyclyl grouphas less than three heteroatoms. More preferably, the heterocyclyl grouphas one to two heteroatoms. In another embodiment, the heterocycloalkylgroup is fused with an aromatic ring. In one embodiment, the nitrogenand sulfur heteroatoms may be optionally oxidized, and the nitrogen atommay be optionally quaternized. The heterocyclic system may be attached,unless otherwise stated, at any heteroatom or carbon atom that affords astable structure.

An example of a 3-membered heterocyclyl group includes, and is notlimited to, aziridine. Examples of 4-membered heterocycloalkyl groupsinclude, and are not limited to, azetidine and a beta lactam. Examplesof 5-membered heterocyclyl groups include, and are not limited to,pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-memberedheterocycloalkyl groups include, and are not limited to, piperidine,morpholine, and piperazine.

Other non-limiting examples of heterocyclyl groups include monocyclicgroups such as aziridine, oxirane, thiirane, azetidine, oxetane,thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane,sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran,thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine,piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran,tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine,homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, andhexamethyleneoxide.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e., having (4n+2) delocalized π (pi) electrons, where n isan integer.

As used herein, the term “aryl,” employed alone or in combination withother terms, means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two, or threerings), wherein such rings may be attached together in a pendent manner,such as a biphenyl, or may be fused, such as naphthalene. Examples ofaryl groups include phenyl, anthracyl, and naphthyl. Preferred examplesare phenyl (e.g., C₆-aryl) and biphenyl (e.g., C₁₂-aryl). In someembodiments, aryl groups have from six to sixteen carbon atoms. In someembodiments, aryl groups have from six to twelve carbon atoms (e.g.,C₆-C₁₂-aryl). In some embodiments, aryl groups have six carbon atoms(e.g., C₆-aryl).

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. Heteroaryl substituents may bedefined by the number of carbon atoms, e.g., C₁-C₉-heteroaryl indicatesthe number of carbon atoms contained in the heteroaryl group withoutincluding the number of heteroatoms. For example, a C₁-C₉-heteroarylwill include an additional one to four heteroatoms. Preferably, theheteroaryl group has less than three heteroatoms. More preferably, theheteroaryl group has one to two heteroatoms. A polycyclic heteroaryl mayinclude one or more rings that are partially saturated. Non-limitingexamples of heteroaryls include pyridyl, pyrazinyl, pyrimidinyl(including, e.g., 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl,pyrrolyl (including, e.g., 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl,pyrazolyl (including, e.g., 3- and 5-pyrazolyl), isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and1,3,4-oxadiazolyl.

Non-limiting examples of polycyclic heterocycles and heteroaryls includeindolyl (including, e.g., 3-, 4-, 5-, 6- and 7-indolyl), indolinyl,quinolyl, tetrahydroquinolyl, isoquinolyl (including, e.g., 1- and5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl(including, e.g., 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl,1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin,1,5-naphthyridinyl, benzofuryl (including, e.g., 3-, 4-, 5-, 6- and7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl(including, e.g., 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl,benzothiazolyl (including, e.g., 2-benzothiazolyl and 5-benzothiazolyl),purinyl, benzimidazolyl (including, e.g., 2-benzimidazolyl),benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl,pyrrolizidinyl, and quinolizidinyl.

As used herein, the term “substituted” means that an atom or group ofatoms has replaced hydrogen as the substituent attached to anothergroup.

As used herein, the terminology “selected from . . . ” (e.g., “R⁴ isselected from A, B and C”) is understood to be equivalent to theterminology “selected from the group consisting of . . . ” (e.g., “R⁴ isselected from the group consisting of A, B and C”).

Compounds

Provided herein are compounds having the structure of Formula I:

or a pharmaceutically acceptable salt thereof.

In embodiments, A is CH₂ or C═O. In embodiments, A is CH₂. In otherembodiments, A is C═O.

R¹ may be H, C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-alkyl-OH, orC₁-C₆-haloalkyl. In embodiments, R¹ is H. In embodiments, R¹ isC₁-C₆-alkyl. In particular embodiments, R¹ is —CH₃. In embodiments, R¹is C₁-C₆-alkenyl. In embodiments, R¹ is C₁-C₆-alkyl-OH. In embodiments,R¹ is C₁-C₆-haloalkyl.

In embodiments, there may be 0, 1, 2, 3, or 4 R² substituents: m is 0,1, 2, 3, or 4. Each R² may be independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR^(B), C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹,C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl,alkylene, cycloalkyl, and heterocycloalkyl are optionally substitutedwith 1, 2, or 3 groups, each independently selected from —OH and halo;or

two R² groups together form a C₃-C₆ spiro cycloalkyl, wherein thecyloalkyl is optionally substituted with 1, 2, or 3 groups, eachindividually selected from —OH and halo.

In certain embodiments, m is 0 and there is no R² substitution. Incertain embodiments, m is 1 and there is one R² substitution. In certainembodiments, m is 2 and there are two R² substitutions. In certainembodiments, m is 3 and there are three R² substitutions. In certainembodiments, m is 4 and there are four R² substitutions.

In certain embodiments, at least one R² is —OH. In certain embodiments,at least one R² is halo. In certain embodiments, at least one R² isC₁-C₆-alkyl. In certain embodiments, at least one R² is C₁-C₆-alkylene.In certain embodiments, at least one R² is C₀-C₆-alkyl-C₃-C₆-cycloalkyl.In certain embodiments, at least one R² isC₀-C₆-alkyl-C₂-C₆-heterocycloalkyl. In certain embodiments, at least oneR² is C₀-C₆-alkyl-OR⁶. In certain embodiments, at least one R² isC₀-C₆-alkyl-N(R)₂. In certain embodiments, at least one R² isC₀-C₆-alkyl-SR⁸. In certain embodiments, at least one R² isC₀-C₆-alkyl-S(O)R. In certain embodiments, at least one R² isC₀-C₆-alkyl-S(O)₂R⁸. In certain embodiments, at least one R² isC₀-C₆-alkyl-C(O)OR⁹. In certain embodiments, at least one R² isC₀-C₆-alkyl-OC(O)R⁹. In certain embodiments, at least one R² isC₀-C₆-alkyl-OC(O)OR⁹. In certain embodiments, at least one R² isC₀-C₆-alkyl-OC(O)N(R⁷)₂. In certain embodiments, at least one R² isC₀-C₆-alkyl-C(O)N(R⁷)₂. In certain embodiments, two R² groups togetherform a C₃-C₆ spiro cycloalkyl, wherein the cyloalkyl is optionallysubstituted with 1, 2, or 3 groups, each individually selected from —OHand halo.

In certain embodiments, R² is substituted with 1, 2 or 3 groups. Eachoccurrence of R² as alkyl, alkylene, cycloalkyl or heterocycloalkyloptionally may be substituted with —OH or halo. For example, R² may bealkyl, and the alkyl is substituted with —OH; or R² may be alkyl, andthe alkyl is substituted with at least one fluorine atom. In aparticular embodiment, R² may be CH₂OH. R² may be alkylene, and thealkylene group is substituted with —OH; or R² may be alkylene, and thealkylene group is substituted with at least one fluorine atom. R² may becycloalkyl, and the cycloalkyl is substituted with —OH; or R² may becycloalkyl, and the cycloalkyl is substituted with at least one fluorineatom. R² may be heterocycloalkyl, and the heterocycloalkyl issubstituted with —OH; or R² may be heterocycloalkyl, and theheterocycloalkyl is substituted with at least one fluorine atom. Incertain embodiments, two R² groups together form a C₃-C₆ spirocycloalkyl, wherein the cyloalkyl is substituted with at least 1 —OH. Incertain embodiments, two R² groups together form a C₃-C₆ spirocycloalkyl, wherein the cyloalkyl is substituted with at least 1halogen.

In certain embodiments, R² may be C₁-C₆-alkyl optionally substitutedwith 1, 2, or 3 halo groups. In certain embodiments, R² may beC₀-C₆-alkyl-OR⁶, wherein R⁶ is C₁-C₆-haloalkyl. In certain embodiments,R² may be (CH₂)₁₋₂—O—C₁-C₃-alkyl, wherein C₁-C₃-alkyl is optionallysubstituted with 1, 2, or 3 halo groups. In certain embodiments, m is 1or 2.

In embodiments, there may be 0, 1, 2, 3, or 4 R³ substituents: n is 0,1, 2, 3, or 4. In certain embodiments, n is 0 and there is no R³substitution. In certain embodiments, n is 1 and there is one R³substitution. In certain embodiments, n is 2 and there are two R³substitutions. In certain embodiments, n is 3 and there are three R³substitutions. In certain embodiments, n is 4 and there are four R³substitutions.

Each R³ may be independently selected from —OH, halo, C₁-C₆-alkyl,C₁-C₆-haloalkyl, O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certainembodiments, at least one R³ is —OH. In certain embodiments, at leastone R³ is halo. In certain embodiments, at least one R³ is C₁-C₆-alkyl.In certain embodiments, at least one R³ is C₁-C₆-haloalkyl. In certainembodiments, at least one R³ is —O—C₁-C₆-alkyl. In certain embodiments,at least one R³ is C₁-C₆-alkyl-OH.

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl,(CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and(CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. Incertain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected from—OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, andC₁-C₆-alkyl-OH. In certain embodiments, R⁴ is(CR^(a)R^(b))_(p)—C₆-C₁₂-aryl optionally substituted with 1, 2, 3, or 4groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. Incertain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected from—OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, andC₁-C₆-alkyl-OH. In certain embodiments, R⁴ is(CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl optionally substituted with 1,2, 3, or 4 groups, each independently selected from —OH, halo, CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. Incertain embodiments, R⁴ is phenyl or pyridyl, wherein said phenyl orpyridyl is is optionally substituted with 1, 2, 3, or 4 groups, eachindependently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl.In a particular embodiment, R⁴ is phenyl, wherein the phenyl issubstituted with 1, 2, 3, or 4 groups, each independently selected fromhalo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl. In another particularembodiment, R⁴ is pyridyl, wherein the pyridyl is substituted with 1, 2,3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyland C₁-C₆-haloalkyl.

R⁵ may be selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In aparticular embodiment, R⁵ is H.

R⁶ may be selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl,and C₀-C₆-alkyl-C₃-C₆-cycloalkyl. In a particular embodiment, R⁶ isselected from H, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

R⁷ may be independently selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C(O) C₁-C₆-alkyl and C₁-C₆-alkyl-OH. In a particular embodiment, R⁷ is,at each occurrence, independently selected from H, and C₁-C₆-alkyl. Inanother embodiment, R⁷ is, at each occurrence, independently selectedfrom C₁-C₆-haloalkyl, and C(O) C₁-C₆-alkyl.

R⁸ may be selected from H and C₁-C₆-alkyl.

R⁹ may be selected from H and C₁-C₆-alkyl.

R^(a) may be independently selected from H, —OH, halo, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH.

R^(b) may be independently selected from H and C₁-C₆-alkyl.

m may be 0, 1, 2, 3, or 4.

n may be 0, 1, 2, 3, or 4.

p may be 0, 1, 2, 3, or 4.

q may be 0 or 1.

a

line denotes an optionally double bond.

In embodiments, A is CH₂ or C═O. In embodiments, A is CH₂. In otherembodiments, A is C═O.

R¹ may be H, C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-alkyl-OH, orC₁-C₆-haloalkyl. In embodiments, R¹ is H. In embodiments, R isC₁-C₆-alkyl. In embodiments, R¹ is C₁-C₆-alkenyl. In embodiments, R¹ isC₁-C₆-alkyl-OH. In embodiments, R is C₁-C₆-haloalkyl.

In embodiments, there may be 0, 1, 2, 3, or 4 R² substituents: m is 0,1, 2, 3, or 4.

Each R² may be independently selected from —OH, halo, C₁-C₆-alkyl,C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R′,C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹,C₀-C₆-alkyl-OC(O)N(R⁷)₂, or C₀-C₆-alkyl-C(O)N(R⁷)₂. In certainembodiments, m is 0 and there is no R² substitution. In certainembodiments, m is 1 and there is one R² substitution. In certainembodiments, m is 2 and there are two R² substitutions. In certainembodiments, m is 3 and there are three R² substitutions. In certainembodiments, m is 4 and there are four R² substitutions.

In certain embodiments, at least one R² is —OH. In certain embodiments,at least one R² is halo. In certain embodiments, at least one R² isC₁-C₆-alkyl. In certain embodiments, at least one R² is C₁-C₆-alkylene.In certain embodiments, at least one R² is C₀-C₆-alkyl-C₃-C₆-cycloalkyl.In certain embodiments, at least one R² isC₀-C₆-alkyl-C₂-C₆-heterocycloalkyl. In certain embodiments, at least oneR² is C₀-C₆-alkyl-OR⁶. In certain embodiments, at least one R² isC₀-C₆-alkyl-N(R)₂. In certain embodiments, at least one R² isC₀-C₆-alkyl-SR⁸. In certain embodiments, at least one R² isC₀-C₆-alkyl-S(O)R. In certain embodiments, at least one R² isC₀-C₆-alkyl-S(O)₂R⁸. In certain embodiments, at least one R² isC₀-C₆-alkyl-C(O)OR⁹. In certain embodiments, at least one R² isC₀-C₆-alkyl-OC(O)R⁹. In certain embodiments, at least one R² isC₀-C₆-alkyl-OC(O)OR⁹. In certain embodiments, at least one R² isC₀-C₆-alkyl-OC(O)N(R⁷)₂. In certain embodiments, at least one R² isC₀-C₆-alkyl-C(O)N(R⁷)₂.

In certain embodiments, R² is substituted with 1, 2 or 3 groups. Eachoccurrence of R² as alkyl, cycloalkyl or heterocycloalkyl optionally maybe substituted with —OH or halo. For example, R² may be alkyl, and thealkyl is substituted with —OH; or R² may be alkyl, and the alkyl issubstituted with at least one fluorine atom. R² may be cycloalkyl, andthe cycloalkyl is substituted with —OH; or R² may be cycloalkyl, and thecycloalkyl is substituted with at least one fluorine atom. R² may beheterocycloalkyl, and the heterocycloalkyl is substituted with —OH; orR² may be heterocycloalkyl, and the heterocycloalkyl is substituted withat least one fluorine atom.

In embodiments, there may be 0, 1, 2, 3, or 4 R³ substituents: n is 0,1, 2, 3, or 4. In certain embodiments, n is 0 and there is no R³substitution. In certain embodiments, n is 1 and there is one R³substitution. In certain embodiments, n is 2 and there are two R³substitutions. In certain embodiments, n is 3 and there are three R³substitutions. In certain embodiments, n is 4 and there are four R³substitutions.

Each R³ may be independently selected from —OH, halo, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certainembodiments, at least one R³ is —OH. In certain embodiments, at leastone R³ is halo. In certain embodiments, at least one R³ is C₁-C₆-alkyl.In certain embodiments, at least one R³ is C₁-C₆-haloalkyl. In certainembodiments, at least one R³ is —O—C₁-C₆-alkyl. In certain embodiments,at least one R³ is C₁-C₆-alkyl-OH.

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl,(CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and(CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. Incertain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected from—OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, O—C₁-C₆-alkyl, andC₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(b))_(p)—C₆-C₁₂-aryloptionally substituted with 1, 2, 3, or 4 groups, each independentlyselected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is(CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl optionally substituted with 1, 2, 3,or 4 groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. Incertain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyloptionally substituted with 1, 2, 3, or 4 groups, each independentlyselected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is phenylor pyridyl, wherein said phenyl or pyridyl is is optionally substitutedwith 1, 2, 3, or 4 groups, each independently selected from halo, —CN,C₁-C₆-alkyl and C₁-C₆-haloalkyl. In a particular embodiment, R⁴ isphenyl, wherein the phenyl is substituted with 1, 2, 3, or 4 groups,each independently selected from halo, —CN, C₁-C₆-alkyl andC₁-C₆-haloalkyl. In another particular embodiment, R⁴ is pyridyl,wherein the pyridyl is substituted with 1, 2, 3, or 4 groups, eachindependently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl.

R⁵ may be selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In aparticular embodiment, R⁵ is H.

R⁶ may be selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl,and C₀-C₆-alkyl-C₃-C₆-cycloalkyl. In a particular embodiment, R⁶ isselected from H, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

R⁷ may be independently selected from H, C₁-C₆-alkyl, andC₁-C₆-alkyl-OH. In a particular embodiment, R⁷ is, at each occurrence,independently selected from H, and C₁-C₆-alkyl.

R⁸ may be selected from H and C₁-C₆-alkyl.

R⁹ may be selected from H and C₁-C₆-alkyl.

R^(a) may be independently selected from H, —OH, halo, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH.

R^(b) may be independently selected from H and C₁-C₆-alkyl.

m may be 0, 1, 2, 3, or 4.

n may be 0, 1, 2, 3, or 4.

p may be 0, 1, 2, 3, or 4.

q may be 0 or 1.

A

line denotes an optionally double bond.

In an embodiment of the compound of Formula I, A is C═O.

In another embodiment of the compound of Formula I, A is CH₂. In anembodiment of the compound of Formula I, q is 1.

In another embodiment of the compound of Formula I, R is H, C₁-C₆-alkyl,or C₁-C₆-haloalkyl. Ina particular embodiment, R is C₁-C₆-alkyl. Inanother particular embodiment, R¹ is —CH₃ or —CH₂CHF₂. In a moreparticular embodiment, R¹ is —CH₃

In another embodiment of the compound of Formula I, R⁴ is phenyl orpyridyl, wherein said phenyl or pyridyl is optionally substituted with1, 2, 3, or 4 groups, each independently selected from halo, —CN,C₁-C₆-alkyl and C₁-C₆-haloalkyl, and R⁵ is H.

In another particular embodiment of Formula I, R¹ is C₁-C₆-alkyl; R² isC₁-C₆-alkyl or C₀-C₆-alkyl-OR⁶, wherein alkyl is substituted with halo,and R⁶ is H or C₁-C₆-haloalkyl; R³ is C₁-C₆-alkyl; R⁴ is phenylsubstituted with 1 or 2 groups, each independently selected from haloand —CN; R is H; m is 1; and n is 1.

In another particular embodiment of Formula I, R¹ is methyl; R² is —CH₂For CH₂—O—CH₂CHF₂; R³ is methyl; R⁴ is phenyl substituted with 1 or 2groups, each independently selected from F and —CN; R⁵ is H; m is 1; andn is 1.

In another particular embodiment of Formula I, R¹ is C₁-C₆-alkyl, R² is—CH₂F, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl issubstituted with 1-3 groups independently selected from halo, —CN, —SF₅,C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, and n is 0.

In another particular embodiment of Formula I, R¹ is C₁-C₆-alkyl, R² is—CH₂OCH₂CHF₂, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl issubstituted with 1-3 groups independently selected from halo, —CN, —SF₅,C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, n is 1, and R³ isC₁-C₆-alkyl.

In another embodiment, the compound of Formula I has the structure ofFormula II

or a pharmaceutically acceptable salt thereof.

In one embodiment of the compound of Formula II, R¹ is H, C₁-C₆-alkyl,or C₁-C₆-haloalkyl. In a particular embodiment, R¹ is C₁-C₆-alkyl. Inanother particular embodiment, R¹ is —CH₃ or —CH₂CHF₂. In a moreparticular embodiment, R¹ is —CH₃.

In another embodiment of the compound of Formula II, R⁴ is phenyl orpyridyl, wherein said phenyl or pyridyl is optionally substituted with1, 2, 3, or 4 groups, each independently selected from halo, —CN,C₁-C₆-alkyl and C₁-C₆-haloalkyl, and R⁹ is H.

In another embodiment, the compound of Formula I or Formula II has thestructure of Formula III:

or a pharmaceutically acceptable salt thereof,

wherein m is 0, 1, or 2.

In one embodiment of the compound of Formula III, R¹ is H, C₁-C₆-alkyl,or C₁-C₆-haloalkyl. In a particular embodiment, R¹ is C₁-C₆-alkyl. Inanother particular embodiment, R¹ is —CH₃ or —CH₂CHF₂. In a moreparticular embodiment, R¹ is —CH₃

In another embodiment of the compound of Formula III, R⁴ is phenyl orpyridyl, wherein said phenyl or pyridyl is optionally substituted with1, 2, 3, or 4 groups, each independently selected from halo, —CN,C₁-C₆-alkyl and C₁-C₆-haloalkyl, and R⁵ is H.

In another embodiment, provided herein are compounds having thestructure of Formula V.

or a pharmaceutically acceptable salt thereof, wherein

A is CH₂ or C═O;

R¹ is H, C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-alkyl-OH, or C₁-C₆-haloalkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹,C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl,alkylene, cycloalkyl, and heterocycloalkyl are optionally substitutedwith 1, 2, or 3 groups, each independently selected from —OH and halo;or

two R² groups together form a C₃-C₆ spiro cycloalkyl, wherein thecyloalkyl is optionally substituted with 1, 2, or 3 groups, eachindividually selected from —OH and halo;

R³ is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl,(CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and(CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁵ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, andC₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is, at each occurrence, independently selected from H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C(O) C₁-C₆-alkyl and C₁-C₆-alkyl-OH;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

R^(a) is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is, at each occurrence, independently selected from H andC₁-C₆-alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4 and

a

line denotes an optionally double bond.

In one embodiment of the compound of Formula V, A is C═O. In anotherembodiment, R¹ is H or C₁-C₆-alkyl. In another embodiment, R is —CH₃. Ina further embodiment, m is 0.

In another embodiment of the compound of Formula V, R⁴ is(CR^(a)R^(b))_(p)—C₁-C₆-heteroaryl or (CR^(a)R^(b))_(p)—C₆-aryl, whereinheteroaryl and aryl are optionally substituted with 1, 2, 3, or 4groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(a) is H or C₁-C₆-alkyl;

R^(b) is H or C₁-C₆-alkyl; and

p is 0 or 1.

In a further embodiment of the compound of Formula V, A is C═O;

R¹ is —CH₃;

R⁴ is (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, wherein aryl is optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected fromhalo, —CN, and C₁-C₆-alkyl;

R⁵ is H;

m is 0;

n is 0; and

p is 0.

In an embodiment of the compound of any one of Formulas I, II, III, orV, m is 0, 1, or 2; and

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkenyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R)₂,C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl,C₀-C₆-alkyl-SR^(B), C₀-C₆-alkyl-S(O)R^(B), C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, and C₀-C₆-alkyl-C(O)N(R)₂, wherein alkyl, alkylene,cycloalkyl, and heterocycloalkyl are optionally substituted with 1 or 2groups, each independently selected from —OH and halo; or

two R² groups together form a C₃-C₆ spiro cycloalkyl, wherein thecyloalkyl is optionally substituted with 1, 2, or 3 groups, eachindividually selected from —OH and halo.

In an embodiment of the compound of any one of Formulas I, II, III, orV, m is 1 or 2; and

R² is, at each occurrence, independently selected from—CH₂N(H)(C(O)—CH₃), —CH₂N(H)CH₂CHF₂, CH₂N(H)CH₂CF₃, or CH(OH)CH═CH₂; ortwo R² groups together form a spiro-cyclobutyl, which is substitutedwith —OH.

In an embodiment of the compound of any one of Formulas I, II, III, orV, m is 0, 1, or 2; and

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkenyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl,C₀-C₆-alkyl-SR^(B), C₀-C₆-alkyl-S(O)R^(B), C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1 or 2groups, each independently selected from —OH and halo.

In an embodiment of the compound of any one of Formulas I, II, III, orV, m is 1 or 2; and

R² is, at each occurrence, independently selected from ═CH₂, —CH₂OH,—OH, —F, —CH₃, —CHF₂, —OCH₃, —OCH₂CH₃, —OCH₂CHF₂, —NH₂, —N(CH₃)₂,morpholinyl, azetidinyl, pyrrolidinyl, —SCH₃, —S(O)CH₃, —S(O)₂CH₃,—CH₂C(O)OCH₃, —CH₂CH₂OH, —C(O)OH, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)NHCH₃,—C(O)N(CH₃)₂, —C(OH)(CH₃)₂, —CH(OH)CH₃, CH(OH)CH₂CH₃, and—CH(OH)-cyclopropyl, wherein morpholinyl, azetidinyl, and pyrrolidinylare optionally substituted with 1 or 2 groups, each independentlyselected from —OH and halo. In an embodiment of the compound of any oneof Formulas I, II, or III, m is 0, 1, or 2; and

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkenyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R)₂,C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl,C₀-C₆-alkyl-SR^(B), C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1 or 2groups, each independently selected from —OH and halo.

In an embodiment of the compound of any one of Formulas I, II, or III, mis 1 or 2; and

R² is, at each occurrence, independently selected from ═CH₂, —CH₂OH,—OH, —F, —CH₃, —CHF₂, —OCH₃, —OCH₂CH₃, —OCH₂CHF₂, —NH₂, —N(CH₃)₂,morpholinyl, azetidinyl, pyrrolidinyl, —SCH₃, —S(O)CH₃, —S(O)₂CH₃,—CH₂C(O)OCH₃, —CH₂CH₂OH, —C(O)OH, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)NHCH₃,—C(O)N(CH₃)₂, —C(OH)(CH₃)₂, —CH(OH)CH₃, CH(OH)CH₂CH₃, and—CH(OH)-cyclopropyl, wherein morpholinyl, azetidinyl, and pyrrolidinylare optionally substituted with 1 or 2 groups, each independentlyselected from —OH and halo.

In an embodiment of the compound of any one of Formulas I, II, or III, nis 0, 1, or 2; and R³ is, at each occurrence, selected from —OH, halo,and C₁-C₆-alkyl.

In an embodiment of the compound of any one of Formula V, n is 0, 1, or2; and R³ is, at each occurrence, selected from —OH, halo, andC₁-C₆-alkyl.

In an embodiment of the compound of any one of Formulas I, II, III, orV, R⁴ is (CR^(a)R^(b))_(p)—C₁-C₅-heteroaryl or(CR^(a)R^(b))_(p)—C₆-aryl, wherein heteroaryl and aryl are optionallysubstituted with 1, 2, or 3 groups, each independently selected from—OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, andC₁-C₆-alkyl-OH;

R^(a) is H or C₁-C₆-alkyl;

R^(b) is H or C₁-C₆-alkyl; and

p is 0 or 1.

In an embodiment of the compound of any one of Formulas I, II, III, orV, R⁴ is C₁-C₅-heteroaryl or C₆-aryl, any of which is optionallysubstituted with 1, 2, or 3 groups, each independently selected fromhalo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

In a further embodiment of the compound of any one of Formulas I, II,III, or V, R⁴ is phenyl or pyridinyl, any of which is optionallysubstituted with 1, 2, or 3 groups, each independently selected fromhalo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

In an embodiment of the compound of any one of Formulas I, II, III, orV, R⁴ is selected from the group consisting of:

In another embodiment of the compound of any one of Formulas I, II, III,or V, R⁴ is selected from the group consisting of:

In another embodiment of the compound of any one of Formulas I, II, III,or V, R⁴ is

In an embodiment of the compound of any one of Formulas I, II, or III,R⁴ is (CR^(a)R^(b))—C₁-C₅-heteroaryl or (CR^(a)R^(b))_(p)—C₆-aryl,wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(a) is H or C₁-C₆-alkyl;

R^(b) is H or C₁-C₆-alkyl; and

p is 0 or 1.

In an embodiment of the compound of any one of Formulas I, II, or III,R⁴ is C₁-C₅-heteroaryl or C₆-aryl, any of which is optionallysubstituted with 1, 2, or 3 groups, each independently selected fromhalo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

In a further embodiment of the compound of any one of Formulas I, II, orIII, R⁴ is phenyl or pyridinyl, any of which is optionally substitutedwith 1, 2, or 3 groups, each independently selected from halo, —CN,C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

In an embodiment of the compound of any one of Formulas I, II, or III,R⁴ is selected from the group consisting of:

In another embodiment of the compound of any one of Formulas I, II, orIII, R⁴ is selected from the group consisting of:

In an embodiment of the compound of any one of Formulas I, II, or III,R⁵ is H or C₁-C₆-alkyl.

In an embodiment of the compound of any one of Formulas I, II, or III,R⁵ is H.

In an embodiment of the compound of any one of Formula V, R⁵ is H orC₁-C₆-alkyl.

In an embodiment of the compound of any one of Formula V, R⁵ is H. In anembodiment of the compound of any one of Formulas I, II, or III,

A is C═O;

R¹ is C₁-C₆-alkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹,C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R)₂, wherein alkyl,alkylene, cycloalkyl, and heterocycloalkyl are optionally substitutedwith 1, 2, or 3 groups, each independently selected from —OH and halo;or

two R² groups together form a C₃-C₆ spiro cycloalkyl, wherein thecyloalkyl is optionally substituted with 1, 2, or 3 groups, eachindividually selected from —OH and halo;

R⁴ is (CR^(a)R^(b))_(p)—C₆-C₂-aryl, wherein aryl is optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected fromhalo, —CN, and C₁-C₆-alkyl;

R⁵ is H;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, andC₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is, at each occurrence, independently selected from H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C(O) C₁-C₆-alkyl and C₁-C₆-alkyl-OH;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

m is 0, 1 or 2;

n is 0;

p is 0; and

q is 1.

In another embodiment of the compound of any one of Formulas I, II, orIII,

A is C═O;

R¹ is C₁-C₆-alkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, and C₀-C₆-alkyl-C(O)N(R)₂, wherein alkyl, alkylene,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,or 3 groups, each independently selected from —OH and halo; or

two R² groups together form a C₃-C₆ spiro cycloalkyl, wherein thecyloalkyl is optionally substituted with 1, 2, or 3 groups, eachindividually selected from —OH and halo;

R⁴ is (CR^(a)R^(b))_(p)—C₆-C₂-aryl, wherein aryl is optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected fromhalo, —CN, and C₁-C₆-alkyl;

R⁵ is H;

R⁶ is selected from H, C₁-C₆-alkyl, and C₁-C₆-haloalkyl;

R⁷ is, at each occurrence, independently selected from H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C(O) C₁-C₆-alkyl and C₁-C₆-alkyl-OH;

R⁸ is C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

m is 0, 1 or 2;

n is 0;

p is 0; and

q is 1.

In an embodiment of the compound of any one of Formulas I, II, or III,

A is C═O;

R¹ is C₁-C₆-alkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹,C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R)₂, wherein alkyl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,or 3 groups, each independently selected from —OH and halo;

R⁴ is (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, wherein aryl is optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected fromhalo, —CN, and C₁-C₆-alkyl;

R⁵ is H;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, andC₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is, at each occurrence, independently selected from H, C₁-C₆-alkyl,and C₁-C₆-alkyl-OH;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

m is 0, 1 or 2;

n is 0;

p is 0; and

q is 1.

In another embodiment of the compound of any one of Formulas I, II, orIII,

A is C═O;

R¹ is C₁-C₆-alkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,or 3 groups, each independently selected from —OH and halo;

R⁴ is (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, wherein aryl is optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected fromhalo, —CN, and C₁-C₆-alkyl;

R⁵ is H;

R⁶ is selected from H, C₁-C₆-alkyl, and C₁-C₆-haloalkyl;

R⁷ is, at each occurrence, independently selected from H, andC₁-C₆-alkyl;

R⁸ is C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

m is 0, 1 or 2;

n is 0;

-   -   p is 0; and

q is 1.

In an embodiment of the compound of any one of Formulas I, II, or III,

A is C═O;

R¹ is C₁-C₆-alkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹,C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,or 3 groups, each independently selected from —OH and halo;

R⁴ is (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, wherein aryl is optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected fromhalo, —CN, and C₁-C₆-alkyl;

R⁵ is H;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, andC₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is, at each occurrence, independently selected from H, C₁-C₆-alkyl,and C₁-C₆-alkyl-OH;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

m is 0, 1 or 2;

n is 0;

p is 0; and

q is 1.

In another embodiment of the compound of any one of Formulas I, II, orIII,

A is C═O;

R¹ is C₁-C₆-alkyl;

R² is, at each occurrence, independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl,C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, and C₀-C₆-alkyl-C(O)N(R)₂, wherein alkyl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2,or 3 groups, each independently selected from —OH and halo;

R⁴ is (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, wherein aryl is optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected fromhalo, —CN, and C₁-C₆-alkyl;

R⁵ is H;

R⁶ is selected from H, C₁-C₆-alkyl, and C₁-C₆-haloalkyl;

R⁷ is, at each occurrence, independently selected from H, andC₁-C₆-alkyl;

R⁸ is C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

m is 0, 1 or 2;

n is 0;

p is 0; and

q is 1.

In another embodiment, the compound of Formula III has the structure ofFormula IV

wherein

m is 1 or 2; and

R² is, at each occurrence, independently selected from—CH₂N(H)(C(O)—CH₃), —CH₂N(H)CH₂CHF₂, —CH₂N(H)CH₂CF₃, and —CH(OH)CH═CH₂;or two R² groups together form a spiro-cyclobutyl, which is substitutedwith —OH. In another embodiment, R² is, at each occurrence,independently selected from ═CH₂, —CH₂OH, —OH, —F, —CH₃, —CHF₂, —OCH₃,—OCH₂CH₃, —OCH₂CHF₂, —NH₂, —N(CH₃)₂, morpholinyl, azetidinyl,pyrrolidinyl, —SCH₃, —S(O)CH₃, —S(O)₂CH₃, —CH₂C(O)OCH₃, —CH₂CH₂OH,—C(O)OH, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)NHCH₃, —C(O)N(CH₃)₂,—C(OH)(CH₃)₂, —CH(OH)CH₃, —CH(OH)CH₂CH₃, and —CH(OH)-cyclopropyl,wherein morpholinyl, azetidinyl, and pyrrolidinyl are optionallysubstituted with 1 or 2 groups, each independently selected from —OH andhalo.

In another embodiment of Formula IV,

m is 1 or 2; and

R² is, at each occurrence, independently selected from ═CH₂, —CH₂OH,—OH, —F, —CH₃, —CHF₂, —OCH₃, —OCH₂CH₃, —OCH₂CHF₂, —NH₂, —N(CH₃)₂,morpholinyl, azetidinyl, pyrrolidinyl, —SCH₃, —S(O)CH₃, —S(O)₂CH₃,—CH₂C(O)OCH₃, —CH₂CH₂OH, —C(O)OH, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)NHCH₃,—C(O)N(CH₃)₂, —C(OH)(CH₃)₂, —CH(OH)CH₃, —CH(OH)CH₂CH₃, and—CH(OH)-cyclopropyl, wherein morpholinyl, azetidinyl, and pyrrolidinylare optionally substituted with 1 or 2 groups, each independentlyselected from —OH and halo.

Provided herein are compounds according to the following embodiments:

In one embodiment of Formula I, A is C═O; R¹ is C₁-C₆-alkyl; R⁴ is(CR^(a)R^(b))_(p)—C₆-C₁₂-aryl substituted with at least one halo; R⁵ isH; n is 0; p is 0; m is 1 or 2; and each R² is independently selectedfrom —OH, halo, C₁-C₆-alkyl, C₁-C₆-alkylene,C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl,C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂, C₀-C₆-alkyl-SR⁸,C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹,C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, orC₀-C₆-alkyl-C(O)N(R⁷)₂. In such an embodiment, if R² is alkyl, alkylene,cycloalkyl or heterocycloalkyl, R² may be substituted with —OH or halo.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂N(H)(C(O)CH₃), R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂N(H)(CH₂CHF₂), R⁴ is phenyl substituted with 1-2 groupsindependently selected from fluorine and CN, R⁵ is H, m is 1, and n is0.

In an embodiment of Formula III, R is C₁-C₆-alkyl, R² is—CH₂N(H)(CH₂CHF₂), R⁴ is phenyl substituted with 1-2 groupsindependently selected from fluorine and CF₃, R⁵ is H, m is 1, and n is0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂N(H)(CH₂CF₃), R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and CN, R⁵ is H, m is 1, and n is 0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂N(H)(CH₂CF₃), R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and CF₃, R⁵ is H, m is 1, and n is 0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is —CH(OH)CH═CH₂,R³ is C₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 groupsindependently selected from fluorine and CF₃, R⁵ is H, m is 1, and nis 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is —CH(OH)CH═CH₂,R³ is C₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 groupsindependently selected from fluorine and CN, R⁵ is H, m is 1, and nis 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is —CH(OH)CH═CH₂,R³ is C₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and bromine, R is H, m is 1, and nis 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂N(H)(CH₂CHF₂), R⁴ is phenyl substituted with 1-3 groupsindependently selected from fluorine and CN, R⁵ is H, m is 1, and n is0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂N(H)(CH₂CHF₂), R⁴ is phenyl substituted with 1-3 groupsindependently selected from fluorine and CF₃, R⁵ is H, m is 1, and n is0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂N(H)(CH₂CHF₂), R⁴ is phenyl substituted with 1-3 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂N(H)(CH₂CHF₂), R⁴ is phenyl substituted with 1-3 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 1, and nis 0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂N(H)(CH₂CHF₂), R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 1, and nis 0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, two R² groupstogether form a spiro-cyclobutyl, which is substituted with —OH, R⁴ isphenyl substituted with 1-2 halogen atoms independently selected fromfluorine and chlorine, R⁵ is H, m is 2, and n is 0.

In one embodiment of Formula I, A is C═O; R¹ is C₁-C₆-alkyl; R⁴ is(CR^(a)R^(b))_(p)—C₆-C₁₂-aryl substituted with at least one halo; R⁵ isH; n is 0; p is 0; m is 1 or 2; and each R² is independently selectedfrom —OH, halo, C₁-C₆-alkyl, C₁-C₆-alkylene,C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl,C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R)₂, C₀-C₆-alkyl-SR^(B),C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹,C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R)₂, orC₀-C₆-alkyl-C(O)N(R)₂. In such an embodiment, if R² is alkyl, cycloalkylor heterocycloalkyl, R² may be substituted with —OH or halo.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂-cyclopropyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In another embodiment of Formula III, R is C₁-C₆-haloalkyl, R² is—CH₂OH, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

Ina further embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—N(H)(C₁-C₆-alkyl), R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In yet another embodiment of Formula III, R¹ is C₁-C₆-alkyl, oneinstance of R² is C₁-C₆-alkyl and the other instance of R² is—C(O)OCH₂CH₃, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 2, andn is 0.

In yet another embodiment of Formula III, R¹ is C₁-C₆-alkyl, oneinstance of R² is C₁-C₆-alkyl and the other instance of R² is —CH₂OH, R⁴is phenyl substituted with 1-2 halogen atoms independently selected fromfluorine and chlorine, R⁵ is H, m is 2, and n is 0.

In a further embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² isC₂-C₆-heterocycloalkyl which is substituted with two fluorine groups, R⁴is phenyl substituted with 1-2 halogen atoms independently selected fromfluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² isC₂-C₆-heterocycloalkyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂—C₂-C₆-heterocycloalkyl, R⁴ is phenyl substituted with 1-2 halogenatoms independently selected from fluorine and chlorine, R⁵ is H, m is1, and n is 0.

In a another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂—C₂-C₆-heterocycloalkyl which is substituted with two fluorinegroups, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a further embodiment of Formula IT, R¹ is C₁-C₆-alkyl, R² is—CH₂N(C₁-C₆-alkyl)(C₁-C₆-alkyl), R⁴ is phenyl substituted with 1-2halogen atoms independently selected from fluorine and chlorine, R⁵ isH, m is 1, and n is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is —CH₂NH₂,R⁴ is phenyl substituted with 1-2 halogen atoms independently selectedfrom fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In yet another embodiment of Formula III, R¹ is C₁-C₆-alkyl, oneinstance of R² is —CH₂CHF₂ and the other instance of R² is —CH₂OH, R⁴ isphenyl substituted with 1-2 halogen atoms independently selected fromfluorine and chlorine, R⁵ is H, m is 2, and n is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₂CH₃, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₂F, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CHF₂, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —C(O)OCH₃,R⁴ is phenyl substituted with 1-2 halogen atoms independently selectedfrom fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a further embodiment of Formula IT, R¹ is C₁-C₆-alkyl, R² is—C(O)N(C₁-C₆-alkyl)(C₁-C₆-alkyl), R⁴ is phenyl substituted with 1-2halogen atoms independently selected from fluorine and chlorine, R⁵ isH, m is 1, and n is 0.

In yet another embodiment of Formula II, R is C₁-C₆-alkyl, R² is CH₂OH,R⁴ is phenyl substituted with 1-2 halogen atoms independently selectedfrom fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In another embodiment of Formula II, R¹ is C₁-C₆-alkyl, one instance ofR² is C₁-C₆-alkyl and the other instance of R² is —CH₂OH, R⁴ is phenylsubstituted with 1-2 halogen atoms independently selected from fluorineand chlorine, R⁵ is H, m is 2, and n is 0.

In another embodiment of Formula I, R¹ is C₁-C₆-alkyl, one instance ofR² is C₁-C₆-alkyl and the other instance of R² is —C(O)OH, R⁴ is phenylsubstituted with 1-2 halogen atoms independently selected from fluorineand chlorine, R⁵ is H, m is 2, and n is 0.

In a further embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —C(O)OH,R⁴ is phenyl substituted with 1-2 halogen atoms independently selectedfrom fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl; R² isC₁-C₆-alkyl or C₀-C₆-alkyl-OR⁶, wherein alkyl is substituted with halo,and R⁶ is H or C₁-C₆-haloalkyl; R³ is C₁-C₆-alkyl; R⁴ is phenylsubstituted with 1 or 2 groups, each independently selected from haloand —CN; R⁵ is H; m is 1; and n is 1.

In another particular embodiment of Formula II, R is methyl; R² is —CH₂For CH₂—O—CH₂CHF₂; R³ is methyl; R⁴ is phenyl substituted with 1 or 2groups, each independently selected from F and —CN; R⁵ is H; m is 1; andn is 1.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is—CH₂F, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl issubstituted with 1-3 groups independently selected from halo, —CN, —SF₅,C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, and n is 0.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is—CH₂OCH₂CHF₂, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl issubstituted with 1-3 groups independently selected from halo, —CN, —SF₅,C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, n is 1, and R³ isC₁-C₆-alkyl.

In a another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂—C₂-C₆-heterocycloalkyl which is substituted with two fluorinegroups, R⁴ is phenyl substituted with 1-2 groups independently selectedfrom fluorine and CF₃, R⁵ is H, m is 1, and n is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is —CH₂NH₂,R⁴ is phenyl substituted with 1-2 groups independently selected fromfluorine and CF₃, R⁵ is H, m is 1, and n is 0.

In a further embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—N(H)(C₁-C₆-alkyl), R⁴ is phenyl substituted with 1-2 groupsindependently selected from fluorine and CF₃, R⁵ is H, m is 1, and n is0.

In a further embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₃, R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and CF₃, R⁵ is H, m is 1, and n is 0.

In a another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂—C₂-C₆-heterocycloalkyl which is substituted with two fluorinegroups, R⁴ is phenyl substituted with 1-2 groups independently selectedfrom fluorine and CN, R⁵ is H, m is 1, and n is 0.

In another embodiment of Formula III, R is C₁-C₆-alkyl, R² is —CH₂NH₂,R⁴ is phenyl substituted with 1-2 groups independently selected fromfluorine and CN, R⁵ is H, m is 1, and n is 0.

In a further embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₃, R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and CN, R⁵ is H, m is 1, and n is 0.

In a further embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CHF₂, R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and CN, R⁵ is H, m is 1, and n is 0.

In a further embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₃, R⁴ is phenyl substituted with 1-3 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a further embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₃, R⁴ is phenyl substituted with 1-3 groups independentlyselected from fluorine and CN, R⁵ is H, m is 1, and n is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₃, R⁴ is phenyl substituted with 1-3 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 1, and nis 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₃, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 1, and nis 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₃, R⁴ is phenyl substituted with 1-3 groups independentlyselected from fluorine and CF₃, R⁵ is H, m is 1, and n is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₃, R⁴ is phenyl substituted with 1-3 fluorine groups, R⁵ isH, m is 1, and n is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)CH₂CH₃, R⁴ is phenyl substituted with 1-4 fluorine groups, R⁵ isH, m is 1, and n is 0.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl-OH, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 0, andn is 1. In a more particular embodiment, R³ is (R)-methyl.

In another embodiment of Formula III, R is C₁-C₆-haloalkyl, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-3 halogen atomsindependently selected from fluorine, bromine, and chlorine, R⁵ is H, mis 0, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-haloalkyl, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 0, andn is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-haloalkyl, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and CF₃, R⁵ is H, m is 0, and n is 1. In a moreparticular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-haloalkyl, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 0, and nis 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-haloalkyl, R³ isC₁-C₆-alkyl, R⁴ is pyridine substituted with 1-2 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 0, and nis 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-haloalkyl, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and CN, R⁵ is H, m is 0, and n is 1. In a moreparticular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-haloalkyl, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and Me, R⁵ is H, m is 0, and n is 1. In a moreparticular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-haloalkyl, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-3 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 0, andn is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, one instance of R²is methyl and the other instance of R² is fluorine, R³ is C₁-C₆-alkyl,R⁴ is phenyl substituted with 1-2 halogen atoms independently selectedfrom fluorine and chlorine, R⁵ is H, m is 2, and n is 1. In a moreparticular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is methyl, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is CH₂OH, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and CF₃, R⁵ is H, m is 1, and n is 1. In a moreparticular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is CH₂OH, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-3 groups independentlyselected from fluorine and CF₃, R⁵ is H, m is 1, and n is 1. In a moreparticular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is CH₂OH, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-3 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 1, and nis 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is CH₂OH, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 1, and nis 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is CH₂OH, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 groups independentlyselected from fluorine and CN, R⁵ is H, m is 1, and n is 1. In a moreparticular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is CH₂OH, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-3 groups independentlyselected from fluorine and CN, R⁵ is H, m is 1, and n is 1. In a moreparticular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is CH₂OH, R³ isC₁-C₆-alkyl, R⁴ is phenyl substituted with 1-3 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-haloalkyl, R² is CH₂OH, R³is C₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is CH(OH)CH₂CH₃,R³ is C₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 groupsindependently selected from fluorine and CF₃, R⁵ is H, m is 1, and nis 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is CH(OH)CH₂CH₃,R³ is C₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 groupsindependently selected from fluorine and CN, R⁵ is H, m is 1, and nis 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R is C₁-C₆-alkyl, R² is CH(OH)CH₂CH₃,R³ is C₁-C₆-alkyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and bromine, R is H, m is 1, and nis 1. In a more particular embodiment, R³ is (R)-methyl

In one embodiment of Formula III, R¹ is C₁-C₆-alkyl, R⁴ is phenylsubstituted with 1-2 halogen atoms independently selected from fluorineand chlorine, R⁵ is H, m is 1, and n is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is fluorine,R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R is C₁-C₆-alkyl, R² is ═CH₂,R⁴ is phenyl substituted with 1-2 halogen atoms independently selectedfrom fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is —CH₂OH, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, oneinstance of R² is —OH and the other instance of R² is —CH₂OH, R⁴ isphenyl substituted with 1-2 halogen atoms independently selected fromfluorine and chlorine, R⁵ is H, m is 2, and n is 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is —OH, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, bothinstances of R² are fluorine, R⁴ is phenyl substituted with 1-2 halogenatoms independently selected from fluorine and chlorine, R⁵ is H, m is2, and n is 0.

In a particular embodiment of Formula III, R is C₁-C₆-alkyl, R² isfluorine, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is fluorine, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 1, and nis 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is fluorine, R⁴ is pyridyl substituted with 1-2 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 1, and nis 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is fluorine, R⁴ is phenyl substituted with 1-2 substituentsindependently selected from fluorine and —CN, R⁵ is H, m is 1, and n is0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is fluorine, R⁴ is phenyl substituted with 1-2 substituentsindependently selected from fluorine and —CH₃, R⁵ is H, m is 1, and n is0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is fluorine, R⁴ is phenyl substituted with 1-2 substituentsindependently selected from fluorine and —CF₃, R⁵ is H, m is 1, and n is0.

In another particular embodiment of Formula III, R is C₁-C₆-alkyl, R² isfluorine, R⁴ is pyridyl substituted with 1-3 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is fluorine, R⁴ is pyridyl substituted with 1-3 halogen atomsindependently selected from fluorine and bromine, R⁵ is H, m is 1, and nis 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₃, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R⁴ isphenyl substituted with 1-2 halogen atoms independently selected fromfluorine and chlorine, R⁵ is H, m is 0, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—OCH₃, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—OCH₂CH₃, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—OCH₂CHF₂, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—NH₂, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—N(CH₃)₂, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² ismorpholin-1-yl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is3,3-difluoroazetidin-1-yl, R⁴ is phenyl substituted with 1-2 halogenatoms independently selected from fluorine and chlorine, R⁵ is H, m is1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² isazetidin-1-yl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² ispyrrolidin-1-yl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—SCH₃, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—S(O)CH₃, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—S(O)₂CH₃, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂C(O)OCH₃, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH₂CH₂OH, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—C(O)OCH₃, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—C(OH)(CH₃)₂, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—C(O)NHCH₃, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—C(O)N(CH₃)₂, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CH(OH)— cyclopropyl, R⁴ is phenyl substituted with 1-2 halogen atomsindependently selected from fluorine and chlorine, R⁵ is H, m is 1, andn is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CHF₂, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In a particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is—CHF₂, R⁴ is phenyl substituted with 1-2 halogen atoms independentlyselected from fluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In another embodiment of Formula III, R¹ is C₁-C₆-haloalkyl, R⁴ isphenyl substituted with 1-2 halogen atoms independently selected fromfluorine and chlorine, R⁵ is H, m is 0, and n is 0.

In an embodiment of Formula I, R¹ is C₁-C₆-alkyl, R⁴ is phenylsubstituted with 1-2 halogen atoms independently selected from fluorineand chlorine, R⁵ is H, m is 0, n is 0, and q is 0.

In an embodiment of Formula II, R is C₁-C₆-alkyl, R² is —CH₃, R⁴ isphenyl substituted with 1-2 halogen atoms independently selected fromfluorine and chlorine, R⁵ is H, m is 1, and n is 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl; R²is C₁-C₆-alkyl or C₀-C₆-alkyl-OR⁶, wherein alkyl is substituted withhalo, and R⁶ is H or C₁-C₆-haloalkyl; R³ is C₁-C₆-alkyl; R⁴ is phenylsubstituted with 1 or 2 groups, each independently selected from haloand —CN; R⁵ is H; m is 1; and n is 1.

In another particular embodiment of Formula III, R¹ is methyl; R² is—CH₂F or CH₂—O—CH₂CHF₂; R³ is methyl; R⁴ is phenyl substituted with 1 or2 groups, each independently selected from F and —CN; R⁵ is H; m is 1;and n is 1.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is —CH₂F, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl issubstituted with 1-3 groups independently selected from halo, —CN, —SF₅,C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, and n is 0.

In another particular embodiment of Formula III, R¹ is C₁-C₆-alkyl, R²is —CH₂OCH₂CHF₂, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridylis substituted with 1-3 groups independently selected from halo, —CN,—SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, n is 1, and R³ isC₁-C₆-alkyl.

In an embodiment of Formula V, R is C₁-C₆-alkyl, R⁴ is phenylsubstituted with 1-2 halogen atoms independently selected from fluorineand chlorine, R⁵ is H, m is 0, and n is 0.

In an embodiment of Formula V, R¹ is C₁-C₆-alkyl, R⁴ is phenylsubstituted with 1-2 halogen atoms independently selected from fluorineand chlorine, R⁵ is H, m is 0, n is 0, and

is a double bond.

In another particular embodiment of Formula V, R¹ is C₁-C₆-alkyl; R² isC₁-C₆-alkyl or C₀-C₆-alkyl-OR⁶, wherein alkyl is substituted with halo,and R⁶ is H or C₁-C₆-haloalkyl; R³ is C₁-C₆-alkyl; R⁴ is phenylsubstituted with 1 or 2 groups, each independently selected from haloand —CN; R⁵ is H; m is 1; and n is 1.

In another particular embodiment of Formula V, R¹ is methyl; R² is —CH₂For CH₂—O—CH₂CHF₂; R³ is methyl; R⁴ is phenyl substituted with 1 or 2groups, each independently selected from F and —CN; R⁵ is H; m is 1; andn is 1.

In another particular embodiment of Formula V, R¹ is C₁-C₆-alkyl, R² is—CH₂F, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl issubstituted with 1-3 groups independently selected from halo, —CN, —SF₅,C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, and n is 0.

In another particular embodiment of Formula V, R¹ is C₁-C₆-alkyl, R² is—CH₂OCH₂CHF₂, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl issubstituted with 1-3 groups independently selected from halo, —CN, —SF₅,C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, n is 1, and R³ isC₁-C₆-alkyl.

Certain embodiments of Formulas I, II, III and IV are shown below inTable 1. disclosed compounds.

TABLE 1

001

002

003

004

005

006

007

008

009

010

011

012

013

014

015

016

017

018

019

020

021

022

023

024

025

026

027

028

029

030

031

032

033

034

035

036

037

038

039

040

041

042

043

044

045

046

In an embodiment, compounds of Formulas I, II, III and IV are selectedfrom:

Com- pound ID Compound Name 001N-(3-chloro-4-fluorophenyl)-10-methyl-8-methylene-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 002 N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 003N-(3-chloro-4-fluorophenyl)-8-hydroxy- 8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 004N-(3-chloro-4-fluorophenyl)-8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 005N-(3-chloro-4-fluorophenyl)-8,8-difluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 006N-(3-chloro-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 007 N-(3-bromo-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 008N-(2-bromo-3-fluoropyridin-4-yl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 009N-(3-cyano-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 0108-fluoro-N-(4-fluoro-3-methylphenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 0118-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 012N-(5-chloro-2,4-difluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 013N-(5-bromo-2,4-difluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 014 N-(3-chloro-4-fluoro-phenyl)-8,10-dimethyl-11-oxo-1,3,4,7,8,9- hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide 015 N-(3-chloro-4-fluoro-phenyl)-10-methyl-11-oxo-1,3,4,7,8,9- hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide 016A (S*)-N-(3-chloro-4-fluorophenyl)-8-methoxy-10-methyl-11-oxo- 3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 016B(R*)-N-(3-chloro-4-fluorophenyl)-8-methoxy-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 017N-(3-chloro-4-fluorophenyl)-8-ethoxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 018N-(3-chloro-4-fluorophenyl)-8-(2,2- difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 0198-amino-N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 020N-(3-chloro-4-fluorophenyl)-8-(dimethylamino)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 021 N-(3-chloro-4-fluorophenyl)-10-methyl-8-morpholino-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 022N-(3-chloro-4-fluorophenyl)-8-(3,3- difluoroazetidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 023 8-(azetidin-1-yl)-N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 024N-(3-chloro-4-fluorophenyl)-10- methyl-11-oxo-8-(pyrrolidin-1-yl)-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 025 N-(3-chloro-4-fluorophenyl)-10-methyl-8-(methylthio)-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 026AN-(3-chloro-4-fluorophenyl)-10- methyl-8-(methylsulfinyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 026BN-(3-chloro-4-fluorophenyl)-10-methyl- 8-(methylsulfinyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 027N-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylsulfonyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-13][1,4]diazepine-2- carboxamide 028methyl 2-(2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepin-8-yl)acetate029 N-(3-chloro-4-fluorophenyl)-8-(2- hydroxyethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 030 ethyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate 031 N2-(3-chloro-4-fluorophenyl)-N8,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2,8-dicarboxamide 032 N2-(3-chloro-4-fluorophenyl)-N8,N8,10-trimethyl-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2,8-dicarboxamide 033N-(3-chloro-4-fluorophenyl)-8-(2-hydroxypropan-2-yl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 034N-(3-chloro-4-fluorophenyl)-8- (1-hydroxyethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 035 N-(3-chloro-4-fluorophenyl)-8-(1-hydroxypropyl)-10-methyl-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 036N-(3-chloro-4-fluorophenyl)-8- (cyclopropyl(hydroxy)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro- 2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 037 N-(3-chloro-4-fluorophenyl)-8-(difluoromethyl)-10-methyl-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 038N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 039 N-(3-chloro-4-fluorophenyl)-9,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 040 methyl 2-(2-((3-chloro-4-fluorophenyl)carbamoyl)-9-methyl-10-oxo-1,2,3,4,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8- carboxylate 041N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-9- methyl-10-oxo-3,4,9,10-tetrahydropyrido[4′,3′:3,4]pyrazolo[1,5- a]pyrazine-2(1H)-carboxamide042 2-((3-chloro-4-fluorophenyl)carbamoyl)-9-methyl-10-oxo-1,2,3,4,9,10- hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8-carboxylic acid 043 methyl2-((3-chloro-4-fluorophenyl)carbamoyl)-9-methyl-10-oxo-1,2,3,4,7,8,9,10-octahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8- carboxylate 044N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-9-methyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5- a]pyrazine-2(1H)- carboxamide045 N-(3-chloro-4-fluorophenyl)-9-methyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide 046 N-(3-chloro-4-fluorophenyl)-10-methyl-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide *Pure but unknown enantiomer ordiastereomer. and pharmaceutically acceptable salts thereof.

Certain embodiments of Formulas I, II, III and IV are shown below inTable 2. disclosed compounds.

TABLE 2

047

048

049

050

051

052

053

054

055

056

057

058

059

060

061

062

063

064

065

066

067

068

069

070

071

072

073

074

075

076

077

078

079

080

081

082

083

084

085

086

087

088

089

090

091

092

093

094

095

096

097

098

099

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

In an embodiment, compounds of Formulas I, II, III and IV are selectedfrom:

Com- pound ID Compound Name 047 N-(3-chloro-4-fluorophenyl)-8-(2-cyclopropyl-1-hydroxyethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro- 2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 048(3R)-N-(3-chloro-4-fluorophenyl)-10-(2-hydroxy-2-methylpropyl)-3-methyl- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 049(3R)-N-(3-chloro-4-fluorophenyl)- 10-(2-hydroxyethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 050 N-(3-chloro-4-fluorophenyl)-10-methyl-8-(methylamino)-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 051N-(3-chloro-4-fluorophenyl)-8- (hydroxymethyl)-11-oxo-10-(2,2,2-trifluoroethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 052ethyl 2-((3-chloro-4-fluorophenyl)carbamoyl)-8,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate 053 N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-8,10-dimethyl-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 054N-(3-chloro-4-fluorophenyl)-8-(3,3-difluoropyrrolidin-1-yl)-10-methyl-11- oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 055N-(3-chloro-4-fluorophenyl)-10- methyl-11-oxo-8-(piperidin-1-yl)-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 056 N-(3-chloro-4-fluorophenyl)-8-(4,4-difluoropiperidin-1-yl)-10-methyl-11- oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 057methyl 2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-9-carboxylate 0582-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylic acid 059N2-(3-chloro-4-fluorophenyl)-N9,N9,10-trimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2,9-dicarboxamide 060N-(3-chloro-4-fluorophenyl)-9- (hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 061 N-(3-chloro-4-fluorophenyl)-9-(hydroxymethyl)-9,10-dimethyl-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 0622-((3-chloro-4-fluorophenyl)carbamoyl)-9,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylic acid 063 N-(3-chloro-4-fluorophenyl)-10-methyl-8-(morpholinomethyl)-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 064N-(3-chloro-4-fluorophenyl)-10-methyl- 11-oxo-8-(piperidin-1-ylmethyl)-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 065 N-(3-chloro-4-fluorophenyl)-8-((dimethylamino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 066 N-(3-chloro-4-fluorophenyl)-8-((3,3-difluoropyrrolidin-1-yl)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 067N-(3-cyano-4-fluorophenyl)-8-((3,3-difluoropyrrolidin-1-yl)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 0688-((3,3-difluoropyrrolidin-1-yl)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2-carboxamide 069N-(3-chloro-4-fluorophenyl)-10-methyl- 11-oxo-8-(pyrrolidin-1-ylmethyl)-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 070 8-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 071(R)-N-(2-bromo-5-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 072(3R)-N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 073(R)-10-(2,2-difluoroethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-methyl- 11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2(7H)-carboxamide 074(R)-N-(3-bromo-4-fluorophenyl)-10- (2,2-difluoroethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 075(R)-N-(2-bromo-3-fluoropyridin-4-yl)-10-(2,2-difluoroethyl)-3-methyl-11- oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2(7H)-carboxamide 076(R)-N-(3-cyano-4-fluorophenyl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 077(R)-10-(2,2-difluoroethyl)-N-(4-fluoro-3-methylphenyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 078(R)-N-(5-chloro-2,4-difluorophenyl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 079_D1(3R,8R*)-N-(3-chloro-4-fluorophenyl)-8-fluoro-3,8,10-trimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 079_D2(3R,8S*)-N-(3-chloro-4-fluorophenyl)-8-fluoro-3,8,10-trimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 080_D1(3R,8S*)-N-(3-chloro-4-fluorophenyl)-3,8,10-trimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 080_D2(3R,8R*)-N-(3-chloro-4-fluorophenyl)-3,8,10-trimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 081_D1(3R,8S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 081_D2(3R,8R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 082_D1(3R,8S*)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo- 3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 082_D2(3R,8R*)-N-(2,4-difluoro-5- (trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 083_D1(3R,8S*)-N-(2,4-difluoro-3- (trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 083_D2(3R,8R*)-N-(2,4-difluoro-3- (trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 084_D1(3R,8S*)-N-(3-bromo-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 084_D2(3R,8R*)-N-(3-bromo-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 085_D1(3R,8S*)-N-(5-bromo-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 085_D2(3R,8R*)-N-(5-bromo-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 086_D1(3R,8S*)-N-(3-bromo-4-fluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 086_D2(3R,8R*)-N-(3-bromo-4-fluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 087_D1(3R,8S*)-N-(3-cyano-4-fluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 087_D2(3R,8R*)-N-(3-cyano-4-fluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 088_D1(3R,8S*)-N-(3-cyano-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 088_D2(3R,8R*)-N-(3-cyano-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 089_D1(3R,8S*)-N-(3-chloro-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 089_D2(3R,8R*)-N-(3-chloro-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 090_D1(3R,8S*)-N-(5-chloro-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 090_D2(3R,8R*)-N-(5-chloro-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 091N-(3-chloro-4-fluorophenyl)-8-(2,2-difluoroethyl)-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 092_D1(3R,8R*)-N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-8-(hydroxymethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 092_D2(3R,8S*)-N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-8-(hydroxymethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 0938-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 094N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-8-((methylamino)methyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 0958-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 096_E1(R*)-N-(5-chloro-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 096_E2(S*)-N-(5-chloro-2,4-difluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 096_E3(S*)-N-(5-chloro-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 096_E4(R*)-N-(5-chloro-2,4-difluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 097_E1(R*)-N-(3-cyano-4-fluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 097_E2(S*)-N-(3-cyano-4-fluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 097_E3(S*)-N-(3-cyano-4-fluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 097_E4(R*)-N-(3cyano-4-fluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 098_E1(R*)-N-(3-cyano-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 098_E2(S*)-N-(3-cyano-2,4-difluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 098_E3(S*)-N-(3-cyano-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 098_E4(R*)-N-(3-cyano-2,4-difluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 099_E1(R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′.3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 099_E2(S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 099_E3(S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 099_E4(R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 100_E1N-(3-chloro-2,4-difluorophenyl)-8-(1- hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 101_E1 N-(3-bromo-2,4-difluorophenyl)-8-(1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 102_E1 N-(3-bromo-4-fluorophenyl)-8-(1-hydroxypropyl)-10-methyl-11-oxo- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 103_E1N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8-(1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 104_E1 8-(1-hydroxypropyl)-10-methyl-11-oxo-N-(3,4,5-trifluorophenyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 105_E1 8-(1-hydroxypropyl)-10-methyl-11-oxo-N-(2,3,4,5-tetrafluorophenyl)- 1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5- a][1,4]diazepine-2-carboxamide 106N-(3-chloro-4-fluorophenyl)-8-(1- hydroxybutyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H- pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 107_D1 1(3R,8S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 2(7H)-carboxamide 107_D2(3R,8R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 108_D1(3R,8S*)-N-(3-cyano-4-fluorophenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 108_D2(3R,8R*)-N-(3-cyano-4-fluorophenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 109_D1(3R,8S*)-N-(3-bromo-4-fluorophenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 109_D2(3R,8R*)-N-(3-bromo-4-fluorophenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 110N-(3-chloro-4-fluorophenyl)-11-methyl-12-oxo-3,4,7,8,9,10,11,12-octahydropyrido[4′,3:3,4]pyrazolo[1,5-a][1,4]diazocine-2(1H)-carboxamide 111(Z)-N-(3-chloro-4-fluorophenyl)-11-methyl-12-oxo-3,4,7,10,11,12-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazocine-2(1H)-carboxamide 112N-(3-cyano-4-fluorophenyl)-8-(3,3-difluoro-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 1132-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine- 7-carboxylic acid 114N-(3-chloro-4-fluorophenyl)-7-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 115N-(3-chloro-4-fluorophenyl)-8-(3-fluoro-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 116N-(3-chloro-4-fluorophenyl)-8-(3,3-difluoro-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide *Pure but unknown enantiomer ordiastereomer.and pharmaceutically acceptable salts thereof.

Certain embodiments of Formulas I, II, III, and IV are shown below inTable 3. disclosed compounds.

TABLE 3

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

In an embodiment, compounds of Formulas I, II, III, and IV are selectedfrom:

Com- pound ID Compound Name 1178-(acetamidomethyl)-N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[41,31:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 118N-(3-cyano-4-fluorophenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 118_E1(R*)-N-(3-cyano-4-fluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 118_E2 (S*)-N-(3-cyano-4-fluorophenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 1198-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 119_E1(R*)-8-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 119_E2(S*)-8-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 120N-(3-cyano-4-fluorophenyl)-10-methyl-11-oxo-8-(((2,2,2-trifluoroethyl)amino)methyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 121N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-8-(((2,2,2-trifluoroethypamino)methyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 122_D1(3R,8S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide122_D2 (3R,8R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide123D_1 (3R,8S*)-N-(3-cyano-4-fluorophenyl)-8-((R)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 123_D2(3R,8R*)-N-(3-cyano-4-fluorophenyl)-8-((R)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′.3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 124_D1(3R,8S*)-N-(3-bromo-4-fluorophenyl)-8-((R)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 124_D2(3R,8R*)-N-(3-bromo-4-fluorophenyl)-8-((R)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 125_E1(R*)-N-(5-bromo-2,4-difluorophenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 125_E2 (S*)-N-(5-bromo-2,4-difluorophenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 126_E1 (R*)-N-(5-chloro-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 126_E2 (S*)-N-(5-chloro-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 127_E1 (R*)-N-(3-cyano-2,4-difluorophenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 127_E2 (S*)-N-(3-cyano-2,4-difluorophenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 128_E1 (R*)-N-(3-chloro-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 128_E2 (S*)-N-(3-chloro-2,4-difluorophenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 129_E1 (R*)-N-(3-bromo-2,4-difluorophenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 129_E2 (S*)-N-(3-bromo-2,4-difluorophenyl)-8(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 130_E1 (R*)-N-(3-bromo-4-fluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 130_E2 (S*)-N-(3-bromo-4-fluorophenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 131_E1(R*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8-(((2,2-difluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 131_E2(S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 132N-(3-chloro-4-fluorophenyl)-3-hydroxy-10′-methyl-11′-oxo-l′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide *Pure butunknown enantiomer or diastereomer. and pharmaceutically acceptablesalts thereof.

Certain embodiments of Formulas I, II, III, and IV are shown below inTable 4. disclosed compounds.

TABLE 4

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

In an embodiment, compounds of Formulas I, II, III, and IV are selectedfrom:

Com- pound ID Compound Name 133_D1(3R,8R*)-8-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 133_D2(3R,8S*)-8-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 134_D1 (3R,8R)-N-(3-Cyano-4-fluorophenyl)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 135_D1(3R,8R)-8-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 134_D2(3R,8S)-N-(3-cyano-4-fluorophenyl)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 135_D2(3R,8S)-8-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 136(R)-N-(3-cyano-4-fluorophenyl)-8,8-difluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. 137_D1(3R,8R*)-N-(3-cyano-4-fluorophenyl)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 137_D2(3R,8S*)-N-(3-Cyano-4-fluorophenyl)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 138(3R,8R*)-8-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 139(R)-N-(3-cyano-4-fluorophenyl)-3,8,8,10-tetramethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 140(R)-N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3,8,8,10-tetramethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 141(R)-N-(3-Cyano-4-fluorophenyl)-3-hydroxy-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide 142(R)-N-(3-Cyano-4-fluorophenyl)-3-fluoro-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H-1,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′- carboxamide 143(R)-N-(3-Cyano-4-fluorophenyl)-3,3-difluoro-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide 144_E1(S)-N-(3-Cyano-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 144_E2(R)-N-(3-Cyano-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 145D_1(R)-N-(3-Cyano-4-fluorophenyl)-8-(2,2-difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 145_D2(S)-N-(3-Cyano-4-fluorophenyl)-8-(2,2-difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 146(R)-N-(3-Cyano-4-fluorophenyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 147(R)-N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 148(3R,8S)-N-(3-Cyano-4-fluorophenyl)-8-(hydroxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)- carboxamide 149(3R,8S)-N-(3-cyano-4-fluorophenyl)-8-(fluoromethyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)- carboxamide 150(3R,8S)-N-(3-cyano-4-fluorophenyl)-8-((2,2-difluoroethoxy)methyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)- carboxamide*Pure but unknown enantiomer or diastereomer. and pharmaceuticallyacceptable salts thereof.

The disclosed disclosed compounds may possess one or more stereocenters,and each stereocenter may exist independently in either the R or Sconfiguration. In one embodiment, compounds described herein are presentin optically active or racemic forms. It is to be understood that thecompounds described herein encompass racemic, optically-active,regioisomeric and stereoisomeric forms, or combinations thereof thatpossess the therapeutically useful properties described herein.

Preparation of optically active forms is achieved in any suitablemanner, including by way of non-limiting example, by resolution of theracemic form with recrystallization techniques, synthesis fromoptically-active starting materials, chiral synthesis, orchromatographic separation using a chiral stationary phase. In oneembodiment, a mixture of one or more isomer is utilized as the disclosedcompound described herein. In another embodiment, compounds describedherein contain one or more chiral centers. These compounds are preparedby any means, including stereoselective synthesis, enantioselectivesynthesis or separation of a mixture of enantiomers or diastereomers.Resolution of compounds and isomers thereof is achieved by any meansincluding, by way of non-limiting example, chemical processes, enzymaticprocesses, fractional crystallization, distillation, and chromatography.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers,” for example, diastereomers, enantiomers, andatropisomers.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof.Within the present disclosure, any open valency appearing on a carbon,oxygen, or nitrogen atom in any structure described herein indicates thepresence of a hydrogen atom. Where a chiral center exists in astructure, but no specific stereochemistry is shown for that center,both enantiomers, separately or as a mixture, are encompassed by thatstructure. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art.

In embodiments, the disclosed compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, and ³⁵S. In one embodiment, isotopically-labeledcompounds are useful in drug or substrate tissue distribution studies.In another embodiment, substitution with heavier isotopes such asdeuterium affords greater metabolic stability (for example, increased invivo half-life or reduced dosage requirements).

In yet another embodiment, substitution with positron emitting isotopes,such as C, ¹⁸F, ¹⁵O and ³N, is useful in Positron Emission Topography(PET) studies for examining substrate receptor occupancy.Isotopically-labeled compounds are prepared by any suitable method or byprocesses using an appropriate isotopically-labeled reagent in place ofthe non-labeled reagent otherwise employed.

In one embodiment, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein and as described, for example, in Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (allof which are incorporated by reference for such disclosure). Generalmethods for the preparation of compound as described herein are modifiedby the use of appropriate reagents and conditions, for the introductionof the various moieties found in the formula as provided herein.

Compounds described herein are synthesized using any suitable proceduresstarting from compounds that are available from commercial sources, orare prepared using procedures described herein.

Methods of Use

Provided herein is a method of treating an HBV infection in anindividual in need thereof, comprising administering to the individual atherapeutically effective amount of a disclosed compound.

Also provided herein is a method of eradicating an HBV infection in anindividual in need thereof, comprising administering to the individual atherapeutically effective amount of a disclosed compound.

Provided herein is a method of reducing HBV viral load associated withan HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of adisclosed compound.

Further, provided herein is a method of reducing reoccurrence of an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a disclosedcompound.

Provided herein is a method of inhibiting or reducing the formation orpresence of HBV DNA-containing particles or HBV RNA-containing particlesin an individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a disclosed compound.

In certain aspects, the methods and/or compositions described herein areeffective for inhibiting or reducing the formation or presence ofHBV-associated particles in vitro or in vivo (e.g., in a cell, in atissue, in an organ (e.g., in the liver), in an organism or the like).HBV-associated particles may contain HBV DNA (i.e., linear and/orcovalently closed circular DNA (cccDNA)) and/or HBV RNA (i.e.,pre-genomic RNA and/or sub-genomic RNA). Accordingly, HBV-associatedparticles include HBV DNA-containing particles or HBV RNA-containingparticles.

As used herein, “HBV-associated particles” refer to both infectious HBVvirions (i.e., Dane particles) and non-infectious HBV subviral particles(i.e., HBV filaments and/or HBV spheres). HBV virions comprise an outerenvelope including surface proteins, a nucleocapsid comprising coreproteins, at least one polymerase protein, and an HBV genome. HBVfilaments and HBV spheres comprise HBV surface proteins, but lack coreproteins, polymerase and an HBV genome. HBV filaments and HBV spheresare also known collectively as surface antigen (HBsAg) particles. HBVspheres comprise middle and small HBV surface proteins. HBV filamentsalso include middle, small and large HBV surface proteins. HBV subviralparticles can include the nonparticulate or secretory HBeAg, whichserves as a marker for active replication of HBV.

Provided herein is a method of reducing an adverse physiological impactof an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of adisclosed compound.

Also provided herein is a method of reducing, slowing, or inhibiting anHBV infection in an individual in need thereof, comprising administeringto the individual a therapeutically effective amount of a disclosedcompound.

Provided herein is a method of inducing reversal of hepatic injury froman HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of adisclosed compound.

Provided herein is a method of reducing the physiological impact oflong-term antiviral therapy for HBV infection in an individual in needthereof, comprising administering to the individual a therapeuticallyeffective amount of a disclosed compound.

Provided herein is a method of prophylactically treating an HBVinfection in an individual in need thereof, wherein the individual isafflicted with a latent HBV infection, comprising administering to theindividual a therapeutically effective amount of a disclosed compound.

In one embodiment, the individual is refractory to other therapeuticclasses of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viralentry inhibitors, viral maturation inhibitors, literature-describedcapsid assembly modulators, antiviral compounds of distinct or unknownmechanism, and the like, or combinations thereof). In anotherembodiment, the disclosed method reduces viral load in an individualsuffering from an HBV infection to a greater extent or at a faster ratecompared to the extent that other therapeutic classes of HBV drugsreduce viral load in the individual.

In one embodiment, the administering of a disclosed compound, or apharmaceutically acceptable salt thereof, allows for administering ofthe at least one additional therapeutic agent at a lower dose orfrequency as compared to the administering of the at least oneadditional therapeutic agent alone that is required to achieve similarresults in prophylactically treating an HBV infection in an individualin need thereof.

In one embodiment, the administering of a disclosed compound, or apharmaceutically acceptable salt thereof, reduces the viral load in theindividual to a greater extent or at a faster rate compared to theadministering of a compound selected from the group consisting of an HBVpolymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and any combination thereof.

In one embodiment, the disclosed method reduces HBV viral load in anindividual suffering from an HBV infection, thus allowing lower doses orvarying regimens of combination therapies to be used.

In one embodiment, the disclosed method causes a lower incidence of HBVviral mutation or HBV viral resistance compared to other classes of HBVdrugs, thereby allowing for long term therapy and minimizing the needfor changes in treatment regimens.

In one embodiment, the administering of a compound the invention, or apharmaceutically acceptable salt thereof, causes a lower incidence ofviral mutation or viral resistance than the administering of a compoundselected from the group consisting of an 1-BV polymerase inhibitor,interferon, viral entry inhibitor, viral maturation inhibitor, distinctcapsid assembly modulator, antiviral compounds of distinct or unknownmechanism, and combination thereof.

In one embodiment, the disclosed method increases the seroconversionrate from HBV infected to non-HBV infected or from detectable HBV viralload to non-detectable HBV viral load beyond that of current treatmentregimens. As used herein, “seroconversion” refers to the period of timeduring which HBV antibodies develop and become detectable.

In one embodiment, the disclosed method increases or normalizes orrestores normal health, elicits full recovery of normal health, restoreslife expectancy, or resolves the viral infection in the individual inneed thereof.

In one embodiment, the disclosed method eliminates or decreases thenumber of HBV RNA particles that are released from HBV infected cellsthus enhancing, prolonging, or increasing the therapeutic benefit of thedisclosed disclosed compounds.

In one embodiment, the disclosed method eradicates HBV from anindividual infected with HBV, thereby obviating the need for long termor life-long treatment, or shortening the duration of treatment, orallowing for reduction in dosing of other antiviral agents.

In another embodiment, the disclosed method further comprises monitoringor detecting the HBV viral load of the subject, and wherein the methodis carried out for a period of time

In one embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula II, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula III, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula IV, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula V, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound of Table1, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound of Table2, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound of Table3, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound of Table4, or a pharmaceutically acceptable salt thereof.

Any of the methods provided herein can further comprise monitoring ordetecting the HBV viral load of the subject, wherein the method iscarried out for a period of time including until such time that the HBVvirus is undetectable.

Combination Therapies

The disclosed compounds may be useful in combination with one or moreadditional compounds useful for treating HBV infection. These additionalcompounds may comprise other disclosed compounds and/or compounds knownto treat, prevent, or reduce the symptoms or effects of HBV infection.Such compounds include, but are not limited to, HBV polymeraseinhibitors, interferons, viral entry inhibitors, viral maturationinhibitors, literature-described capsid assembly modulators, reversetranscriptase inhibitors, immunomodulatory agents, TLR-agonists, andother agents with distinct or unknown mechanisms that affect the HBVlife cycle or affect the consequences of HBV infection.

In non-limiting examples, the disclosed compounds may be used incombination with one or more drugs (or a salt thereof) selected from thegroup comprising:

HBV reverse transcriptase inhibitors, and DNA and RNA polymeraseinhibitors including, but not limited to, lamivudine (3TC, Zeffix,Heptovir, Epivir, and Epivir-HBV), entecavir (Baraclude, Entavir),adefovir dipivoxil (Hepsara, Preveon, bis-POM PMEA), tenofovirdisoproxil fumarate (Viread, TDF or PMPA);

interferons including, but not limited to, interferon alpha (IFN-α),interferon beta (IFN-Q), interferon lambda (IFN-λ), and interferon gamma(IFN-γ);

viral entry inhibitors;

viral maturation inhibitors;

literature-described capsid assembly modulators, such as, but notlimited to, BAY 41-4109;

reverse transcriptase inhibitors;

immunomodulatory agents such as TLR-agonists; and

agents of distinct or unknown mechanisms, such as but not limited toAT-61((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide),AT-130((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide),and similar analogs.

In one embodiment, the additional therapeutic agent is an interferon.The term “interferon” or “IFN” refers to any member of the family ofhighly homologous species-specific proteins that inhibit viralreplication and cellular proliferation and modulate immune response.Human interferons are grouped into three classes: Type I, which includesinterferon-alpha (IFN-α), interferon-beta (IFN-β), and interferon-omega(IFN-ω), Type II, which includes interferon-gamma (IFN-γ), and Type III,which includes interferon-lambda (IFN-λ). Recombinant forms ofinterferons that have been developed and are commercially available areencompassed by the term “interferon” as used herein. Subtypes ofinterferons, such as chemically modified or mutated interferons, arealso encompassed by the term “interferon” as used herein. Chemicallymodified interferons may include pegylated interferons and glycosylatedinterferons. Examples of interferons also include, but are not limitedto, interferon-alpha-2a, interferon-alpha-2b, interferon-alpha-n1,interferon-beta-1a, interferon-beta-b, interferon-lamda-1,interferon-lamda-2, and interferon-lamda-3. Examples of pegylatedinterferons include pegylated interferon-alpha-2a and pegylatedinterferon alpha-2b.

Accordingly, in one embodiment, the compounds of Formula I, II, III, IVor V can be administered in combination with an interferon selected fromthe group consisting of interferon alpha (IFN-α), interferon beta(IFN-β), interferon lambda (IFN-λ), and interferon gamma (IFN-γ). In onespecific embodiment, the interferon is interferon-alpha-2a,interferon-alpha-2b, or interferon-alpha-n1. In another specificembodiment, the interferon-alpha-2a or interferon-alpha-2b is pegylated.In a preferred embodiment, the interferon-alpha-2a is pegylatedinterferon-alpha-2a (PEGASYS). In another embodiment, the additionaltherapeutic agent is selected from immune modulator or immune stimulatortherapies, which includes biological agents belonging to the interferonclass.

Further, the additional therapeutic agent may be an agent of distinct orunknown mechanism including agents that disrupt the function of otheressential viral protein(s) or host proteins required for HBV replicationor persistence.

In another embodiment, the additional therapeutic agent is an antiviralagent that blocks viral entry or maturation or targets the HBVpolymerase such as nucleoside or nucleotide or non-nucleos(t)idepolymerase inhibitors. In a further embodiment of the combinationtherapy, the reverse transcriptase inhibitor or DNA or RNA polymeraseinhibitor is Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine,Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine,Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir,ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir,Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In an embodiment, the additional therapeutic agent is animmunomodulatory agent that induces a natural, limited immune responseleading to induction of immune responses against unrelated viruses. Inother words, the immunomodulatory agent can effect maturation of antigenpresenting cells, proliferation of T-cells and cytokine release (e.g.,IL-12, IL-18, IFN-alpha,-beta, and -gamma and TNF-alpha among others),

In a further embodiment, the additional therapeutic agent is a TLRmodulator or a TLR agonist, such as a TLR-7 agonist or TLR-9 agonist. Infurther embodiment of the combination therapy, the TLR-7 agonist isselected from the group consisting of SM360320(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848 (methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

In any of the methods provided herein, the method may further compriseadministering to the individual at least one HBV vaccine, a nucleosideHBV inhibitor, an interferon or any combination thereof. In anembodiment, the HBV vaccine is at least one of RECOMBIVAX HB, ENGERIX-B,ELOVAC B, GENEVAC-B, or SHANVAC B.

In one embodiment, the methods described herein further compriseadministering at least one additional therapeutic agent selected fromthe group consisting of nucleotide/nucleoside analogs, entry inhibitors,fusion inhibitors, and any combination of these or other antiviralmechanisms.

In another aspect, provided herein is method of treating an HBVinfection in an individual in need thereof, comprising reducing the HBVviral load by administering to the individual a therapeuticallyeffective amount of a disclosed compound alone or in combination with areverse transcriptase inhibitor; and further administering to theindividual a therapeutically effective amount of HBV vaccine. Thereverse transcriptase inhibitor may be at least one of Zidovudine,Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir,Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin,acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir,Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine,Delavirdine, or Etravirine.

In another aspect, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising reducing the HBVviral load by administering to the individual a therapeuticallyeffective amount of a disclosed compound alone or in combination with aantisense oligonucleotide or RNA interference agent that targets HBVnucleic acids; and further administering to the individual atherapeutically effective amount of HBV vaccine. The antisenseoligonucleotide or RNA interference agent possesses sufficientcomplementarity to the the target HBV nucleic acids to inhibitreplication of the viral genome, transcription of viral RNAs, ortranslation of viral proteins.

In another embodiment, the disclosed compound and the at least oneadditional therapeutic agent are co-formulated. In yet anotherembodiment, the disclosed compound and the at least one additionaltherapeutic agent are co-administered. For any combination therapydescribed herein, synergistic effect may be calculated, for example,using suitable methods such as the Sigmoid-E_(max) equation (Holford &Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of Loeweadditivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv.Enzyme Regul. 22: 27-55). Each equation referred to above may be appliedto experimental data to generate a corresponding graph to aid inassessing the effects of the drug combination. The corresponding graphsassociated with the equations referred to above are theconcentration-effect curve, isobologram curve and combination indexcurve, respectively.

In an embodiment of any of the methods of administering combinationtherapies provided herein, the method can further comprise monitoring ordetecting the HBV viral load of the subject, wherein the method iscarried out for a period of time including until such time that the HBVvirus is undetectable.

Administration/Dosage/Formulations

In another aspect, provided herein is a pharmaceutical compositioncomprising a at least one disclosed compound, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety offactors including the activity of the particular compound employed, thetime of administration, the rate of excretion of the compound, theduration of the treatment, other drugs, compounds or materials used incombination with the compound, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skillin the art may readily determine and prescribe the effective amount ofthe pharmaceutical composition required. For example, the physician orveterinarian could begin administration of the pharmaceuticalcomposition to dose the disclosed compound at levels lower than thatrequired in order to achieve the desired therapeutic effect andgradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulatethe compound in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the patients tobe treated; each unit containing a predetermined quantity of thedisclosed compound calculated to produce the desired therapeutic effectin association with the required pharmaceutical vehicle. The dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the disclosed compound and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding/formulating such a disclosed compound for thetreatment of HBV infection in a patient.

In one embodiment, the compositions of the invention are formulatedusing one or more pharmaceutically acceptable excipients or carriers. Inone embodiment, the pharmaceutical compositions of the inventioncomprise a therapeutically effective amount of a disclosed compound anda pharmaceutically acceptable carrier.

In some embodiments, the dose of a disclosed compound is from about 1 mgto about 2,500 mg. In some embodiments, a dose of a disclosed compoundused in compositions described herein is less than about 10,000 mg, orless than about 8,000 mg, or less than about 6,000 mg, or less thanabout 5,000 mg, or less than about 3,000 mg, or less than about 2,000mg, or less than about 1,000 mg, or less than about 500 mg, or less thanabout 200 mg, or less than about 50 mg. Similarly, in some embodiments,a dose of a second compound (i.e., another drug for HBV treatment) asdescribed herein is less than about 1,000 mg, or less than about 800 mg,or less than about 600 mg, or less than about 500 mg, or less than about400 mg, or less than about 300 mg, or less than about 200 mg, or lessthan about 100 mg, or less than about 50 mg, or less than about 40 mg,or less than about 30 mg, or less than about 25 mg, or less than about20 mg, or less than about 15 mg, or less than about 10 mg, or less thanabout 5 mg, or less than about 2 mg, or less than about 1 mg, or lessthan about 0.5 mg, and any and all whole or partial increments thereof.

In one embodiment, the present invention is directed to a packagedpharmaceutical composition comprising a container holding atherapeutically effective amount of a disclosed compound, alone or incombination with a second pharmaceutical agent; and instructions forusing the compound to treat, prevent, or reduce one or more symptoms ofHBV infection in a patient.

Routes of administration of any of the compositions of the inventioninclude oral, nasal, rectal, intravaginal, parenteral, buccal,sublingual or topical. The compounds for use in the invention may beformulated for administration by any suitable route, such as for oral orparenteral, for example, transdermal, transmucosal (e.g., sublingual,lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- andperivaginally), (intra)nasal and (trans)rectal), intravesical,intrapulmonary, intraduodenal, intragastrical, intrathecal,subcutaneous, intramuscular, intradermal, intra-arterial, intravenous,intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

For oral application, particularly suitable are tablets, dragees,liquids, drops, suppositories, or capsules, caplets and gelcaps. Thecompositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from the group consisting of inert, non-toxicpharmaceutically excipients that are suitable for the manufacture oftablets. Such excipients include, for example an inert diluent such aslactose; granulating and disintegrating agents such as cornstarch;binding agents such as starch; and lubricating agents such as magnesiumstearate. The tablets may be uncoated or they may be coated by knowntechniques for elegance or to delay the release of the activeingredients. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertdiluent.

For parenteral administration, the disclosed compounds may be formulatedfor injection or infusion, for example, intravenous, intramuscular orsubcutaneous injection or infusion, or for administration in a bolusdose or continuous infusion. Suspensions, solutions or emulsions in anoily or aqueous vehicle, optionally containing other formulatory agentssuch as suspending, stabilizing or dispersing agents may be used.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

Examples

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Abbreviations and acronyms used herein include the following:

Term Acronym Acetonitrile ACN or MeCN Aqueous aq Atmosphere atmtert-Butylcarbamoyl Boc Boron-dipyrromethene BODIPY Benzyl Bn Broad brCapside assembly CA Carboxybenzyl CBz Diatomaceous Earth Celite ®1,1′-Carbonyldiimidazole CDI Doublet of doublets dd Diethylaminosulfurtrifluoride DAST Di-tert-butyl azodicarboxylate DBAD1,8-Diazabicyclo[5.4.0]undec-7-ene DBU Dichloroethane DCEDichloromethane DCM Bis(2-methoxyethyl)aminosulfur trifluorideDeoxo-Fluor ® Diethyl azodicarboxylate DEAD Diisopropyl azodicarboxylateDIAD Diisopropylethylamine DIPEA, DIEA, or Hunig′s base4-Dimethylaminopyridine DMAP 1,2-Dimethoxyethane DMEN,N-Dimethylformamide DMF Dimethyl sulfide DMS Dimethylsulfoxide DMSODeoxyribonucleic Acid DNA 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimideEDCI, EDAC, or EDC Diethyl ether Ether, Et₂O Ethyl Acetate EtOAc, or EAEthanol EtOH Electrospray ionization ESI Normal-phase silica gelchromatography FCC Grams g Hours h or hr(1-[Bis(dimethylamino)methylene]- HATU 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) Hepatitis B Virus HBV Aceticacid HOAc 1-Hydroxy-7-azabenzotriazole HOAt Hydroxybenzotriazole HOBtHigh-pressure liquid chromatography HPLC Hertz Hz Isopropyl alcoholiPrOH, IPA Potassium tert-butoxide KOtBu Lithium aluminum hydride LAHLiquid chromatography and mass spectrometry LCMS Lithiumdiisopropylamide LDA Lithium bis(trimethylsilyl)amide LHMDS Molar Mmultiplet m Mass to charge ratio m/z meta-Chloroperoxybenzoic acid mCPBAMethyl Iodide Mel Methanol MeOH Milligrams mg Megahertz MHz Minute minMilliliter mL Microliter μL Millimole mmol Micromole μmol Massspectrometry MS Mesityl chloride MsCl Normal N Sodium acetate NaOAcSodium tert-butoxide NaOt-Bu N-Methylmorpholine N-oxide NMO Nuclearmagnetic resonance NMR CF₃SO₃− or triflate OTf Polymerase chain reactionPCR Petroleum ether PE Palladium (II) acetate Pd(OAc)₂Palladium(II)bis(triphenylphosphine) dichloride Pd(PPh₃)₂Cl₂Tetrakis(triphenylphosphine)palladium(0) Pd(PPh₃)₄ [1,1′-Bis(di-tert-PdCl₂(dtbpf) or butylphosphino)ferrocene]dichloropalladium(II)Pd(dtbpf)₂Cl₂ [1,1′- PdCl₂(dppf) orBis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)₂Cl₂9-(2-Phosphonyl-methoxypropyly)adenine PMPA Parts per million ppmPrecipitate ppt Polytetrafluoroethylene PTFE Pyridine PyBenzotriazol-1-yl-oxytripyrrolidinophosphonium PyBOP hexafluorophosphateRetention time R_(t) Ribonucleic Acid RNA Room temperature rt singlet sSaturated sat 1-Chloromethyl-4-fluoro-1,4- Selectfluor ®diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)12-(Trimethylsilyl)ethoxy]methyl acetal SEM Supercritical FluidChromatography SFC Temperature T triplet t Propylphosphonic anhydrideT₃P Tert-Butyl alcohol tBuOH, t-BuOH Tetra-n-butylammonium fluoride TBAFTetra-n-butylammonium iodide TBAI Tert-butyldiphenylsilyl chlorideTBDPSCl Triethylamine TEA Trifluoroacetic acid TFA Tetrahydrofuran THFThin layer chromatography TLC Toll-like receptor TLR Tumor necrosisfactor TNF Volume in milliliters of solvent per gram of substrate V, orvolumes (Diethylamino)difluorosulfonium tetrafluoroborate XtalFluor ®

Preparative Examples

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

According to SCHEME 1, a commercially available or syntheticallyaccessible compound of formula (Xa), where R is C₁₋₆alkyl orC₁₋₆haloalkyl, and PG is a suitable nitrogen protecting group such asBOC, Bn, and the like, is alkylated with an alkylating agent such asethyl prop-2-enoate, ethyl 2-(bromomethyl)prop-2-enoate, and the like,to provide a compound of formula (XI), where R^(b) is C₂₋₆alkyleneoptionally substituted with CO₂Et. A compound of formula (Xa), whereR^(a) is CH₃ or CH₂CHF₂, and PG is BOC, is alkylated under conditionsknown to one skilled in the art, for example, reaction with or without abase such as NaH, Cs₂CO₃, K₂CO₃, and the like, in a suitable solventsuch as THF, DMF and the like, with an alkylating agent such as ethyl2-(bromomethyl)prop-2-enoate and the like, at temperatures ranging from0° C. to 80° C., for a period of 12-24 h, to provide a compound offormula (XI), where R^(b) is CH₂(C═CH₂)CO₂Et. In an alternate method, acompound of formula (Xb), is first alkylated under conditions previouslydescribed, then protected with a suitable nitrogen protecting group, toprovide a compound of formula (XI). For example, a compound of formula(Xb), where R^(a) is C₁₋₆alkyl, is alkylated with an alkylating agentsuch as 5-methylene-1,3,2-dioxathiane 2-oxide, in a solvent such as THF,and the like, at a temperature of about 50-80° C., subsequent protectionwith di-tert-butyl dicarbonate, provides a compound of formula (XI),where R^(b) is CH₂(C═CH₂)CH₂OH, and PG is BOC.

Deprotection of the nitrogen protecting group, employing conditionsknown to one skilled in the art provides a compound of formula (XII).For example the BOC protecting group is removed with acid such as TFA,HCl, and the like, in a suitable solvent such as DCM, and the like.

According to SCHEME 2, a commercially available or syntheticallyaccessible compound of formula (XIII), where R³ is H or C₁₋₆alkyl, iscoupled with a compound of formula (XII), where R^(a) is C₁₋₆alkyl orC₁₋₆haloalkyl, and R^(b) is CH₂CH₂OH, CH(CH₃)CH₂CH₂OH, CH(C═CH₂)CO₂Et,CH₂CH(C═CH₂)CH₂OH, CH₂CH₂CH(OPG)CO₂Me, CH₂CH(CH₂OH)CH(OTBDPS)CH═CH₂,CH₂C(CH₂OH)(CH₂CH(OBn)CH₂), CH₂CH₂CH(OH)CO₂Me, CH₂C(Me)₂CH₂OH,CH(CH₂OTBS)(CH₂OCH₂CH═CH₂), and the like, under amide bond couplingconditions to provide a compound of formula (XIV). For example, an acidcompound of formula (XIII) is reacted with an amine of formula (XII), inthe presence of a dehydrating agent such as HOBt/EDAC, CDI, PyBOP, HATU,HOAT, propylphosphonic anhydride (T₃P), a suitably selected base such asDIPEA, TEA, and the like, in a solvent such as toluene, MeCN, EtOAc,DMF, THF, DCM, or a mixture thereof, to afford a compound of formula(XIV).

A compound of formula (XIV), where R³ is H or C₁₋₆alkyl, R^(a) isC₁₋₆alkyl or C₁₋₆haloalkyl, and R^(b) is CH(C═CH₂)CO₂Et, is reacted witha base such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), in a solventsuch as ACN, at a temperature of about 40-60° C. for a period of 1-3 hprovides a compound of formula (XVa).

A compound of formula (XIV) is cyclized under Mitsonobu conditions, toprovide a compound of formulas (XVb) where R⁴ is H, (XVc), and (XVd).For example, a compound of formula (XIV), where R³ is H or C₁₋₆alkyl,R^(a) is C₁₋₆alkyl or C₁₋₆haloalkyl, and R is CH₂CH₂OH is reacted with atrisubstituted phosphane such as triphenylphosphane, tributylphosphane,and the like, and an azodicarboxylate such as diethyl azodicarboxylate(DEAD), diisopropyl azodicarboxylate (DIAD), and the like, in a suitablesolvent such as THF, and the like, at temperatures ranging from 70-100°C., for a period of 10-16 hours, to provide a compound of formula (XVb),where R¹ and R³ are C₁₋₆alkyl or C₁₋₆haloalkyl.

A compound of formula (XIV), where R³ is H or C₁₋₆alkyl, R is C₁₋₆alkylor C₁₋₆haloalkyl, and R is CH₂CH₂CH(OH)CO₂Me, is reacted with a basesuch as TEA, and a sulfonyl such as MsCl, in a solvent such as DCM, at atemperature of about 0° C. for a period of 1-3 h. This is followed by abase such as NaH in a solvent such as THF to provide a compound offormula (XVe).

A compound of formula (XIV), where R³ is H or C₁₋₆alkyl, R^(a) isC₁₋₆alkyl or C₁₋₆haloalkyl, and R^(b) is CH₂C(CH₂OH)(CH₂CH(OBn)CH₂), isreacted with a base such as TEA, and a sulfonyl such as MsCl, in asolvent such as DCM, at a temperature of about 0° C. for a period of 1-3h. This is followed by a base such as NaH in a solvent such as THF toprovide a compound of formula (XVf).

A compound of formula (XIV), where R³ is H or C₁₋₆alkyl, R^(a) isC₁₋₆alkyl or C₁₋₆haloalkyl, and R^(b) is CH₂CH(CH₂OH)CH(OTBDPS)CH═CH₂,is reacted with a base such as TEA, and a sulfonyl such as MsCl, in asolvent such as DCM, at a temperature of about 0° C. for a period of 1-3h. This is followed by a base such as NaH in a solvent such as THF toprovide a compound of formula (XVg).

A compound of formula (XIV), where R³ is H or C₁₋₆alkyl, R is C₁₋₆alkylor C₁₋₆haloalkyl, and R^(b) is CH₂CH(C═CH₂)CH₂OH, is reacted with a basesuch as TEA, and a sulfonyl such as MsCl, in a solvent such as DCM, at atemperature of about 0° C. for a period of 1-3 h. This is followed by abase such as potassium tert-butoxide in a solvent such as DMF. Followedby a reducing agent such palladium on carbon in the presence of hydrogengas in a solvent such as methanol, at a temperature of about 30° C., forabout 15-45 minutes provides a compound of formula (XVh).

A compound of formula (XIV), where R³ is H or C₁₋₆alkyl, R^(a) isC₁₋₆alkyl or C₁₋₆haloalkyl, and R^(b) is CH₂C(Me)₂CH₂OH, is reacted witha base such as TEA, and a sulfonyl such as MsCl, in a solvent such asDCM, at a temperature of about 0° C. for a period of 1-3 h. This isfollowed by a base such as sodium hydride in a solvent such as THF toprovide a compound of formula (XVi).

A compound of formula (XVb), where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, and R⁴ is CH₂OH, is prepared in three steps. First, acompound of formula (XIV) where R^(b) is CH(CH₂OTBS)(CH₂OCH₂CH═CH₂) isdeprotected using a suitable reagent such as TBAF, in a solvent such asTHF, to provide a compound of formula (XIV) where R^(b) isCH(CH₂OH)(CH₂OCH₂CH═CH₂). Second, cyclized under the Mitsonobuconditions described above. Third, removal of the allyl group usingsuitable reagents such as osmium oxide, with sodium periodate, and withNMO, in a solvent such as THF, to provide a compound of formula (XVb),where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl, and R⁴ isCH₂OH.

A compound of formula (XVb), where where R³ is H or C₁₋₆alkyl, R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl, and R⁴ is CH₂OH, is reacted with afluorinating reagent such as DAST, in a solvent such as DCM, to providea compound of formula (XVb), where where R³ is H or C₁₋₆alkyl, R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl, and R⁴ is CH₂F.

A compound of formula (XVb), where where R³ is H or C₁₋₆alkyl, R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl, and R⁴ is CH₂OH, is reacted with aalkylating reagent such as CF₂HCH₂OTf, using a base such as sodiumhydride, in a solvent such as THF, to provide a compound of formula(XVb), where where R³ is H or C₁₋₆alkyl, R is C₁₋₆alkyl orC₁₋₆haloalkyl, and R⁴ is CH₂OCH₂CHF₂.

According to SCHEME 3, a compound of formula (XVd) is oxidized,employing oxidation conditions known to one skilled in the art, forexample OSO₄ and NaIO₄.

A compound of formula (XVI), where R is C₁₋₆alkyl or C₁₋₆haloalkyl andR³ is H or C₁₋₆alkyl, is reduced with a reducing agent such as NaBH₄,and the like, in a suitable solvent such as MeOH, THF, and the like, toprovide a compound of formula (XVII), where R² is OH, and m is 1.

A compound of formula (XVII), where R² is OH, and m is 1, is alkylatedwith an alkylating agent such as a C₁₋₆alkylhalide or C₁₋₆haloalkylhalide, and the like, a base such as NaH, and the like, in a suitablesolvent such as such as THF, DMF, and the like, to provide a compound offormula (XVII), where R² is OC₁₋₆alkyl or O—C₁₋₆haloalkyl, and m is 1.

A compound of formula (XVII), where R² is OH, and m is 1, is fluorinatedwith a fluorinating agent such as, DAST, XtalFluor®, Deoxo-Fluor, andthe like, in a suitable solvent such as DCM, and the like, attemperatures ranging from −78° C. to 50° C., for a period of 2-16 h, toprovide a compound of formula (XVII), where R² is F, and m is 1.

A compound of formula (XVII), where R² is S—C₁₋₆alkyl, and m is 1, isprepared in three steps from a compound of formula (XVII) where R² isOH, and m is 1. In a first step, mesylation of a compound of formula(XVII) where R² is OH, with mesyl chloride, a base such as TEA, in asolvent such as DCM, to provide a compound of formula (XVII), where R²is O—SO₂CH₃. Subsequent reaction of the mesylated compound of formula(XVII) with sodium methanethiolate, in a solvent such as DMF, attemperatures ranging from 0° C. to 20° C., provides a compound offormula (XVII), where R² is S(C═O)CH₃. Reaction of a compound of formula(XVII), where R² is S(C═O)CH₃ with a base such as K₂CO₃, and the like,and an C₁₋₆alkylhalide such as Mel, provides a compound of formula(XVII), where R² is S—C₁₋₆alkyl.

A carbonyl compound of formula (XVI), where R¹ is C₁₋₆alkyl orC₁₋₆haloalkyl and R³ is H or C₁₋₆alkyl, is fluorinated with afluorinating agent such as, DAST, XtalFluor®, Deoxo-Fluor®, and thelike, in a suitable solvent such as DCM, and the like, at temperaturesranging from −78° C. to 50° C., for a period of 2-16 h, to provide acompound of formula (XVII), where R² is F, and m is 2.

A carbonyl compound of formula (XVI), where R¹ is C₁₋₆alkyl orC₁₋₆haloalkyl and R³ is H or C₁₋₆alkyl, is reacted with an alkyl amineof formula N(C₁₋₆alkyl)₁-2 such as NH(CH₃)₂, or an optionallysubstituted C₂-C₆-heterocycloalkyl such as morpholine, azetidine,difluoroazetidine, pyrrolidine, and the like, under reductive aminationconditions, to provide a compound of formula (XVII), where R² is anoptionally substituted C₂-C₆-heterocycloalkyl, or N(C₁₋₆alkyl)₂.

For example, a carbonyl compound of formula (XVI), where R¹ is C₁₋₆alkylor C₁₋₆haloalkyl and R³ is H or C₁₋₆alkyl, is reacted with NH(CH₃)₂, areducing agent such as NaCNBH₃, NaBH₃, sodium triacetxyborohydride, andthe like, with or without a dehydrating agent such as molecular sieves,with or without HOAc, or NaOAc, in a suitable solvent such as DCM, THF,DCE, and the like, provides a compound of formula (XVI) where R² isN(CH₃)₂.

A compound of formula (XVII), where R² is CH₂CO₂C₁₋₆alkyl, is preparedin two steps from a carbonyl compound of formula (XVI), where R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl and R³ is H or C₁₋₆alkyl. In a first step,carbonyl compound of formula (XVI) is reacted with methyl2-dimethoxyphosphorylacetate, a base such as potassium2-methylpropan-2-olate, in a solvent such as THF, and the like, attemperatures ranging from 0° C. to 20° C. In a second step, reduction ofthe alkene under hydrogenation conditions, for example, Pd/C and H₂, ina solvent such as EtOH, MeOH, and the like, provides a compound offormula (XVII), where R² is CH₂CO₂CH₃.

A compound of formula (XVII), where R² is CH₂N(C₁₋₆alkyl)₁₋₂ such asNH(CH₃)₂, CH₂N(C₁₋₆haloalkyl)₁₋₂, or an optionally substitutedCH₂C₂-C₆-heterocycloalkyl such as morpholine, azetidine,difluoroazetidine, pyrrolidine, and the like, is prepared in three stepsfrom a carbonyl compound of formula (XVI), where R¹ is C₁₋₆alkyl orC₁₋₆haloalkyl and R³ is H or C₁₋₆alkyl. In a first step, carbonylcompound of formula (XVI) is reacted with a hydroboranation reagent suchas wilkinson's catalyst and catecholborane, a base such as sodiumhydroxide, in a solvent such as hydrogen peroxide, at temperaturesranging from −30° C. to 20° C. In a second step, mesylation of acompound of formula (XVII) where R² is CH₂OH, with mesyl chloride, abase such as TEA, in a solvent such as DCM, to provide a compound offormula (XVII), where R² is CH₂O—SO₂CH₃. Subsequent reaction of themesylated compound of formula (XVII) with a C₂-C₆-heterocycloalkyl, in asolvent such as DMSO, at temperatures ranging from 80° C. to 90° C.,provides a compound of formula (XVII), where R² is CH₂N(C₁₋₆alkyl)₁₋₂such as NH(CH₃)₂, CH₂N(C₁₋₆haloalkyl)₁₋₂, or an optionally substitutedCH₂C₂-C₆-heterocycloalkyl such as morpholine, azetidine,difluoroazetidine, pyrrolidine, and the like.

A compound of formula (XVII), where R² is F and C₁₋₆alkyl, and m is 2,is prepared from a compound of formula (XVII) where R² is OH andC₁₋₆alkyl, and m is 2 with a fluorinating agent such as, DAST,XtalFluor®, Deoxo-Fluor®, and the like, in a suitable solvent such asDCM, and the like, at temperatures ranging from −78° C. to 50° C., for aperiod of 2-16 h, to provide a compound of formula (XVII), where R² is Fand C₁₋₆alkyl, and m is 2.

A compound of formula (XVII), where R² isCH₂N(C₁₋₆haloalkyl)(COC₁₋₆haloalky), and m is 1, is prepared from acompound of formula (XVII), where R² is CH₂N(C₁₋₆haloalkyl)H by reactingwith an acylating reagent such as trifluoroacetic anhydride, a base suchas trietyl amine, in a solvent such as DCM, at a temperature between therange of 0° C. to 20° C., for a period of 2-4 hours, to provide acompound of formula (XVII), where R² isCH₂N(C₁₋₆haloalkyl)(COC₁₋₆haloalky), and m is 1.

According to SCHEME 4, a commercially available or syntheticallyaccessible alkyl halide, where X is a halide and G¹ is CH₂C(CH₂C)═CH₂,CH₂CH₂CH₂N(H)(Boc), and CH₂CH₂CH(NHCbz)CO₂Me and the like, is coupledwith a compound of formula (XVIII), where R³ is H or C₁₋₆alkyl, undercoupling conditions to provide a compound of formula (XIX). For example,a compound of formula (XVIII) is reacted with an alkyl halide, asuitably selected base such as potassium carbonate and the like, in asolvent such as DMF or THF, to afford a compound of formula (XIX).

A compound of formula (XIX), where R³ is H or C₁₋₆alkyl, is reacted witha primary a C₁₋₆alkyl or C₁₋₆haloalkyl amine such as methyl amine, in asolvent such as EtOH, at a temperature of about 80° C. for a period of16 h provides a compound of formula (XVd) where R¹ is C₁₋₆alkyl orC₁₋₆haloalkyl.

A compound of formula (XXa), where R³ is H or C₁₋₆alkyl, and R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl, is made in three steps. The first beingglobal deprotection of BOC protecting groups of a compound of Formula(XIX) where G¹ is CH₂CH₂CH₂N(H)(Boc), using suitable conditions such asTFA in DCM. Second, cyclizing by forming an amide bond using a suitablebase such as potassium carbonate, in a solvent such as EtOH, andreprotecting with boc anhydride to form a compound of Formula (XXa)where R¹ is H. Third, reacting a C₁₋₆alkyl or C₁₋₆haloalkyl halide,using a base such as NaH, in a solvent such as THF, to provide acompound of Formula (XXa) where R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl.

A compound of formula (XXb), where R³ is H or C₁₋₆alkyl, and R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl, is made in four steps. The first beingdeprotection of the Cbz protecting group of a compound of Formula (XIX)where G¹ is CH₂CH₂CH(NHCbz)CO₂Me, using suitable deprotection conditionssuch as Pd/C in the presense of H₂, in a solvent such as MeOH. Second,cyclizing by forming an amide bond and subsequent hydrolysis, using abase such as sodium methoxide, and a solvent such as methanol. Third,esterification of the carboxylic acid, using a base such as NaH, alkylhalid such as methyl iodide, and a solvent such as DMF. Fourth, reactinga C₁₋₆alkyl or C₁₋₆haloalkyl halide, using a base such as NaH, in asolvent such as THF, to provide a compound of Formula (XXb) where R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl.

According to SCHEME 5, a compound of Formula (XXI) where R³ is H orC₁₋₆alkyl, R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl, and Ar is an optionallysubstituted aryl ring can be prepared in two steps. For example, the Bocprotecting group can be removed from a compound of Formula (XXIa) usingsuitable conditions such as trifluoroacetic acid in DCM. The resultingproduct can then be reacted with an aryl carbamate such asN-Aryl-phenylcarbamate, a base such as TEA, and a solvent such as DCM toprovide a compound of Formula (XXI) where R³ is H or C₁₋₆alkyl, R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl, and Ar is an optionally substituted arylring. Wherein, a compound of Formula (XXIa) is a compound of Formula(XXb), Formula (XVa), or Formula (XVe).

According to SCHEME 6, a compound of Formula (XXI) where R³ is H orC₁₋₆alkyl, R is C₁₋₆alkyl or C₁₋₆haloalkyl, and Ar is4-fluoro-2-chloro-benzene, is reacted with a Grignard reagent such asmethyl magnesium bromide, in a solvent such as THF to provide a compoundof Formula (XXII) where R² is an optionally substituted C₁₋₆alkyl, and mis 1.

A compound of Formula (XXI) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, and Ar is 4-fluoro-2-chloro-benzene, is reacted withan alkyl amine of formula N(C₁₋₆alkyl)₁₋₂ such as NH(CH₃)₂, in a solventsuch as DMF, with a base such as DIPEA, and a coupling agent such asHATU to provide a compound of Formula (XXII) where R² is CON(C₁₋₆alkyl)₁₋₂, and m is 1.

A compound of Formula (XXII) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, and Ar is 4-fluoro-2-chloro-benzene, R² isCH(OH)C₁₋₆alkyl or CH(OH)C₃₋₆cycloalkyl, and m is 1, was prepared from acompound of Formula (XXI) in 4 steps. First, a compound of Formula (XXI)was hydrolyzed, using a base such as sodium hydroxide, in a solvent suchas water, MeOH or a mix of both to provide a compound of Formula (XXII)where R² is COOH. Second, reacting with an alkyl alkoxy amide suchMeNHOMe, a coupling reagent such as HATU, a base such as DIPEA, and asolvent such as DMF to provide a compound of Formula (XXII) where R² isa Weinreb amide. Third, reacting with a Grignard such as methylmagnesium bromide, ethyl magnesium bromide or cyclopropyl magnesiumbromide, and a solvent such as THF to provide a compound of Formula(XXII) where R² is C═OMe. Fourth, reacting with a reducing reagent suchas NaBH₄, and a solvent such as EtOH to provide a compound of Formula(XXII) where R² is CH(OH)C₁₋₆alkyl or CH(OH)C₃₋₆cycloalkyl, and m is 1.

A compound of Formula (XXII) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, and Ar is 4-fluoro-2-chloro-benzene, R² is CHF₂, and mis 1, was prepared from a compound of Formula (XXI) in 3 steps. First, acompound of Formula (XXI) was reduced, using a reducing reagent such asLiAlH₄, in a solvent such as THF to provide a compound of Formula (XXII)where R² is CH₂OH. Second, reacting with an oxidant such DMP, in asolvent such as DCM to provide a compound of Formula (XXII) where R² isCHO. Third, reacting with a fluorinating agent such as DAST, in asolvent such as DCM to provide a compound of Formula (XXII) where R² isCHF₂, and m is 1.

According to SCHEME 7, a compound of Formula (XXIII) where R³ is H orC₁₋₆alkyl, R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl, and Ar is an optionallysubstituted aryl ring can be prepared in two steps. For example, the Bocprotecting group can be removed from a compound of Formula (XXIIIa)using suitable conditions such as trifluoroacetic acid in DCM. Theresulting product can then be reacted with an aryl carbamate such asN-Aryl-phenylcarbamate, a base such as TEA, and a solvent such as DCM toprovide a compound of Formula (XXIII) where R³ is H or C₁₋₆alkyl, R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl, and Ar is an optionally substituted arylring. Wherein, a compound of Formula (XXIIIa) is prepared as describedin SCHEME 3.

According to SCHEME 8, a compound of Formula (XXIII) where R³ is H orC₁₋₆alkyl, R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl, and Ar is4-fluoro-2-chloro-benzene, is reacted with an oxidant such as (Bu₃Sn)₂Oand Bromide or m-CPBA, in a solvent such as DCM to provide a compound ofFormula (XXIV) where R² is a sulfonate or sulfoxide, and m is 1.

According to SCHEME 9, a compound of Formula (XXV) where R³ is H orC₁₋₆alkyl, R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl, and Ar is an optionallysubstituted aryl ring can be prepared in two steps. For example, the Bocprotecting group can be removed from a compound of Formula (XXVa) usingsuitable conditions such as trifluoroacetic acid in DCM. The resultingproduct can then be reacted with an aryl carbamate such asN-Aryl-phenylcarbamate, a base such as TEA, and a solvent such as DCM toprovide a compound of Formula (XXV) where R³ is H or C₁₋₆alkyl, R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl, and Ar is an optionally substituted arylring. Wherein, a compound of Formula (XXVa) is prepared as described inSCHEME 3.

According to SCHEME 10, a compound of Formula (XXIV) where R³ is H orC₁₋₆alkyl, R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl, and Ar is4-fluoro-2-chloro-benzene, R² is N(C₁₋₆alkyl)₀₋₂, and m is 1, wasprepared from a compound of Formula (XXV) in 3 steps. First, a compoundof Formula (XXV) where n is 0 was reacted with, sulfonating reagent suchas MSCl, using a base such as TEA, in a solvent such as DCM to provide acompound of Formula (XXIV) where R² is OMs. Second, reacting with anucleophilic azide such as sodium azide, in a solvent such as DMF toprovide a compound of Formula (XXIV) where R² is N₃. Third, reactingwith a reducing agent such as zinc/ammoniumchloride or Pd/C andhydrogen, in a solvent such as MeOH, EtOH, water, or a mixture of any toprovide a compound of Formula (XXII) where R² is N(C₁₋₆alkyl)₀₋₂, and mis 1.

A compound of Formula (XXIV) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, and Ar is 4-fluoro-2-chloro-benzene, R² isN(C₁₋₆alkyl)-2, and m is 1, was prepared from a compound of Formula(XXV) in 3 steps. First, a compound of Formula (XXV) where n is 1 wasreacted with, sulfonating reagent such as MSCl, using a base such asTEA, in a solvent such as DCM to provide a compound of Formula (XXIV)where R² is CH₂OMs. Second, reacting with a nucleophilic azide such assodium azide, in a solvent such as DMF to provide a compound of Formula(XXIV) where R² is CH₂N₃. Third, reacting with a reducing agent such aszinc/ammoniumchloride or Pd/C and hydrogen, in a solvent such as MeOH,EtOH, water, or a mixture of any to provide a compound of Formula (XXIV)where R² is CH₂N(C₁₋₆alkyl)₀₋₂, and m is 1.

According to SCHEME 11, a compound of Formula (XXVIII) where R³ is H orC₁₋₆alkyl, R¹ is C₁₋₆alkyl-OH was prepared from a compound of Formula(XXVII) in 2 steps. First, a compound of Formula (XXVII) where wasreacted with, alkylating reagent with a terminal ester such asBrCH₂COOMe, using a base such as NaH, in a solvent such as THF toprovide a compound of Formula (XXVI) where R¹ is a C₁-C₆alkyl ester.Second, reacting with a Grignard such as methyl magnesium bromide, in asolvent such as THE to provide a compound of Formula (XXVI) where R² isC₁-C₆ alkyl-OH.

A compound of Formula (XXVIII) where R³ is H or C₁₋₆alkyl, R¹ isC₁₋₆alkyl-OH was prepared from a compound of Formula (XXVII) in 2 steps.First, a compound of Formula (XXVII) where was reacted with, alkylatingreagent with a terminal ester such as BrCH₂COOMe, using a base such asNaH, in a solvent such as THF to provide a compound of Formula (XXVI)where R¹ is a C₁-C₆alkyl ester. Second, reacting with a reducing reagentsuch as LiAlH₄, in a solvent such as THE to provide a compound ofFormula (XXVI) where R² is C₁-C₆ alkyl-OH.

According to SCHEME 12, a compound of Formula (XXIX) where R³ is H orC₁₋₆alkyl, and R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl, is reacted with astrong base such as LDA, an alkylating agent such as Mel or CHF₂CH₂OTf,in a solvent such as THF to provide a compound of Formula (XXX) where R²is C₁₋₆alkyl or C₁₋₆haloalkyl and COOalkyl, and m is 2.

A compound of Formula (XXX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, R² is CH(OH)Et, and m is 1 was prepared from acompound of Formula (XXIX) in 5 steps. First, a compound of Formula(XXIX) where was hydrolyzed using suitable conditions such as NaOH inMeOH/water to provide a compound of Formula (XXX) where R² is COOH.Second, reacting with an alkyl alkoxy amide such MeNHOMe, a couplingreagent such as HATU, a base such as DIPEA, and a solvent such as DMF toprovide a compound of Formula (XXX) where R² is a Weinreb amide. Third,reacting with a grignard such as vinyl magnesium bromide, in a solventsuch as THE to provide a compound of Formula (XXX) where R² isC(O)CH═CH₂. Fourth, reacting with a reducing reagent such asNaBH₄/CeCl₃, in a solvent such as MeOH to provide a compound of Formula(XXX) where R² is CH(OH)CH═CH₂. Fifth, reacting with a reducing reagentsuch as Pd/C, in a solvent such as MeOH to provide a compound of Formula(XXX) where R² is CH(OH)CH₂CH₃, and m is 1.

A compound of Formula (XXX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, R² is CH(OH) C₁₋₆alkyl, and m is 1 was prepared from acompound of Formula (XXX) where R² is a Weinreb amide in 2 steps. First,reacting with a C₁₋₆alkyl Grignard such as n-propyl magnesium bromide,in a solvent such as THF to provide a compound of Formula (XXX) where R²is C(O)C₁₋₆alkyl. Second, reacting with a reducing reagent such asNaBH₄, in a solvent such as MeOH to provide a compound of Formula (XXX)where R² is CH(OH) C₁₋₆alkyl.

A compound of Formula (XXX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, R² is CH(OH)CH₂-cyclopropyl, and m is 1 was preparedfrom a compound of Formula (XXX) where R² is a Weinreb amide in 3 steps.First, reacting with a grignard such as allyl magnesium bromide, in asolvent such as THE to provide a compound of Formula (XXX) where R² isC(O)CH₂CH═CH₂. Second, reacting with a reducing reagent such as NaBH₄,in a solvent such as MeOH to provide a compound of Formula (XXX) whereR² is CH(OH) CH₂CH═CH₂. Third, reacting with an alkyl halide such asICH₂Cl, a zincate such as diethyl zinc, in a solvent such as DCM toprovide a compound of Formula (XXX) where R² is CH(OH)CH₂-cyclopropyl.

A compound of Formula (XXX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, R² is CH₂OH and F, and m is 2 was prepared from acompound of Formula (XXIX) in 2 steps. First, reacting with afluorinating reagent such as NFSI with LDA, in a solvent such as THE toprovide a compound of Formula (XXX) where R² is C(O)C₁₋₆alkyl and F. andm is 2. Second, reacting with a reducing reagent such as LiBH₄, in asolvent such as THE to provide a compound of Formula (XXX) where R² isCH₂OH and F, and m is 2.

A compound of Formula (XXX) where R³ is H or C₁₋₆alkyl, R is C₁₋₆alkylor C₁₋₆haloalkyl, R² is CH₂OC₁₋₆haloalkyl, and m is 1 was prepared froma compound of Formula (XXX) where R² is a Weinreb amide in 2 steps.First, reacting with a reducing agent such as NaBH₄, in a solvent suchas THE to provide a compound of Formula (XXX) where R² is CH₂OH. Second,reacting with an alkylating reagent such as CHF₂CH₂OTf, using a suitablebase such as NaH, in a solvent such as THE to provide a compound ofFormula (XXX) where R² is CH₂OC₁₋₆haloalkyl.

According to SCHEME 13, a compound of Formula (XXXI) where R³ is H orC₁₋₆alkyl, R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl, and R² is C₁₋₆alkyl orC₁₋₆haloalkyl, is reacted with a reducing agent such as LiBH₄, in asolvent such as THE to provide a compound of Formula (XXXII) where R² isC₁₋₆alkyl or C₁₋₆haloalkyl and CH₂OH, and m is 2.

A compound of Formula (XXXI) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkylor C₁₋₆haloalkyl, and R² is C₁₋₆alkyl or C₁₋₆haloalkyl, is hydrolyzedusing suitable conditions such as NaOH in MeOH/water to provide acompound of Formula (XXXII) where R² is C₁₋₆alkyl or C₁₋₆haloalkyl andCOOH, and m is 2.

According to SCHEME 13, a compound of Formula (XVf) where R³ is H orC₁₋₆alkyl, and R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl, is reacted with aflurorinating agent such as DAST, in a solvent such as DCM to provide acompound of Formula (XXXV) where R⁴ is F, and m is 1.

A compound of Formula (XXXV) where R³ is H or C₁₋₆alkyl, and R¹ isC₁₋₆alkyl or C₁₋₆haloalkyl, and R⁴ is F and F, and m is 2, is preparedin two steps. First, a compound of Formula (XVf) is oxidized using asuitable reagent such as DMP, in a solvent such as DCM, to provide acompound of Formula (XXXV) where R⁴ is ═O. Second, reacting with aflurorinating agent such as DAST, in a solvent such as DCM to provide acompound of Formula (XXXV) where R⁴ is F and F, and m is 2.

According to SCHEME 15, a compound of Formula (XXXIV) where R³ is H orC₁₋₆alkyl, R¹ is as described by the schemes above, R² is described asthe schemes above, Ar is an optionally substituted aryl ring, and m is0, 1, or 2 is prepared in two steps. First, removal of the Bocprotecting group from a compound of Formula (XXXIII) using suitableconditions such as trifluoroacetic acid in DCM. Second, reaction with aaryl carbamate such as N-Aryl-phenylcarbamate, a base such as TEA, and asolvent such as DCM to provide a compound of Formula (XXXIV) where R³ isH or C₁₋₆alkyl, R¹ is as described by the schemes above, R² is describedas the schemes above, Ar is an optionally substituted aryl ring, and mis 0, 1, or 2.

Intermediate 1. Tert-Butyl10-methyl-8-methylene-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate

Method A

Step 1. 5-methylene-1,3,2-dioxathiane 2-oxide. To a solution of2-methylenepropane-1,3-diol (5.00 g, 56.75 mmol, 4.63 mL, 1.00 eq) inCCl₄ (50.00 mL) was added a solution of SOCl₂ (10.13 g, 85.13 mmol, 6.18mL, 1.50 eq) in CCl₄ (10.00 mL) at 0° C. under N₂, and the mixture wasstirred at 0° C. for 45 mins. The mixture was concentrated under reducedpressure to afford 5-methylene-1,3,2-dioxathiane 2-oxide (6.90 g, 51.43mmol, 90.63% yield) as yellow oil, which was used directly for the nextstep. ¹H NMR (400 MHz, CDCl₃) δ 5.36-5.39 (m, 2H), 5.16 (s, 2H),4.22-4.28 (m, 2H).

Step 2. 2-((methylamino)methyl)prop-2-en-1-ol. A solution of5-methylene-1,3,2-dioxathiane 2-oxide (1.00 g, 7.45 mmol, 1.00 eq) andmethanamine (2 M, 11.18 mL, 3.00 eq) in THE (2.00 mL) was heated to 70°C. for 16 h. TLC (DCM/MeOH=20/1) showed the starting material wasconsumed completely and one major new spot with larger polarity wasdetected. The mixture was filtered and the filtrate was concentrated invacuo to afford the title compound (750.00 mg, 7.41 mmol, 99.46% yield)as yellow oil, which was used directly for the next step.

Step 3. tert-butyl (2-(hydroxymethyl)allyl)(methyl)carbamate. To asolution of 2-(methylaminomethyl)prop-2-en-1-ol (750.00 mg, 7.41 mmol,1.00 eq) in dioxane (5.00 mL)/H₂O (5.00 mL) was added Boc₂O (1.94 g,8.89 mmol, 2.04 mL, 1.20 eq) and NaHCO₃ (622.40 mg, 7.41 mmol, 1.00 eq).The mixture was stirred at 30° C. for 16 h. The mixture with was dilutedwith EA (50 mL) and washed with brine (50 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated to give yellow oil, whichwas purified by silica gel column to afford the title compound (710.00mg, 3.53 mmol, 47.61% yield) as yellow oil. ¹H NMR (400 MHz, CD₃OD) δ5.10 (s, 1H), 4.97 (s, 1H), 3.91-4.10 (m, 4H), 2.81 (s, 3H), 1.50 (s,9H).

Step 4. 2-((methylamino)methyl)prop-2-en-1-ol hydrochloride. To asolution of tert-butyl N-[2-(hydroxymethyl)allyl]-N-methyl-carbamate(710.00 mg, 3.53 mmol, 1.00 eq) in dioxane (3.00 mL) was addedHCl/dioxane (4 M, 5.00 mL, 5.67 eq) and the mixture was stirred at 15°C. for 1 h. TLC (PE/EtOAc=2/1) showed the starting material was consumedcompletely and one major new spot with larger polarity was detected. Themixture was concentrated in vacuo to afford the title compound (480.00mg, 3.49 mmol, 98.81% yield, HCl) as yellow oil, which was used directlyfor the next step. ¹H NMR (400 MHz, CD₃OD) δ 5.46 (s, 1H), 5.32 (s, 1H),4.20 (s, 2H), 3.71 (s, 2H), 2.73 (s, 3H).

Step 5. tert-butyl3-((2-(hydroxymethyl)allyl)(methyl)carbamoyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.A mixture of 5-tert-butoxycarbonyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (550.00 mg, 2.06 mmol, 1.00 eq), DIPEA(798.70 mg, 6.18 mmol, 1.08 mL, 3.00 eq), HATU (939.93 mg, 2.47 mmol,1.20 eq) and 2-(methylaminomethyl)prop-2-en-1-ol (425.21 mg, 3.09 mmol,1.50 eq, HCl) in DMF (6.00 mL) was heated to 80° C. for 16 h. Themixture was diluted with EtOAc (80 mL) and washed with brine (80 mL*3).The organic phase was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give yellow oil. The yellow oil was purified bysilica gel column to afford the title compound (390.00 mg, 1.11 mmol,54.03% yield) as yellow solid. LCMS: 351 [M+1].

Step 6. tert-butyl10-methyl-8-methylene-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxylate.To a solution of tert-butyl3-[2-(hydroxymethyl)allyl-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(200.00 mg, 570.76 μmol, 1.00 eq) and triphenylphosphane (194.62 mg,741.99 μmol, 1.30 eq) in THF (3.00 mL) was added DIAD (150.04 mg, 741.99μmol, 144.27 μL, 1.30 eq) and the mixture was stirred at 30° C. for 4 h.The mixture was diluted with EtOAc (50 mL) and washed with HCl (1 M, 50mL). The organic phase was dried over Na₂SO₄, filtered and concentratedin vacuo to give oil. The oil was purified by silica gel column toafford the title compound as impure product (320.00 mg, crude,containing Ph₃PO) as yellow oil. LCMS: 355 [M+23].

Method B

Step 1. 5-tert-butyl 3-ethyl2-(2-(chloromethyl)allyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate.To a solution of 3-chloro-2-(chloromethyl)prop-1-ene (7.62 g, 60.95mmol, 7.05 mL, 3.00 eq) in DMF (100.00 mL) was added 5-tert-butyl3-ethyl 2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate(6.00 g, 20.32 mmol, 1.00 eq) and K₂CO₃ (3.65 g, 26.41 mmol, 1.30 eq).The mixture was stirred at 25° C. for 6 h and then heated to 75° C. for16 h. TLC showed the starting material was consumed completely. Themixture was diluted with EtOAc (80 mL), washed with HCl (1M, 80 mL) andbrine (80 mL*2). The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo to give yellow oil. The oil was purified by silicagel column to afford the title compound (2.90 g, 7.55 mmol, 37.18%yield) as colorless oil.

Step 2. tert-butyl10-methyl-8-methylene-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxylate.A solution of 5-tert-butyl 3-ethyl2-(2-(chloromethyl)allyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate(1.00 g, 2.61 mmol, 1.00 eq) and methanamine (7.5 M, 40.00 mL, 33%purity, 114.94 eq) in EtOH (30.00 mL) was heated to 80° C. in sealedtube for 16 h. The mixture was concentrated in vacuo to give yellow oil.The yellow oil was purified by silica gel column to afford the titlecompound (560.00 mg, 1.68 mmol, 64.37% yield) as yellow oil. LCMS: 333[M+1].

Intermediate 2. Tert-Butyl10-methyl-8,11-dioxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxylate

To a solution of tert-butyl10-methyl-8-methylene-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(150.00 mg, 451.26 μmol, 1.00 eq) in THF (3.00 mL) and H₂O (1.50 mL) wasadded OsO₄ (5.74 mg, 22.56 μmol, 1.17 μL, 0.05 eq) and NaIO₄ (386.08 mg,1.81 mmol, 100.02 μ μL, 4.00 eq) at 0° C. The mixture was stirred at 15°C. for 16 hr. The mixture was diluted with EtOAc (40 mL) and washed withbrine (40 mL). The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo to give yellow oil. The yellow oil was purified bysilica gel column to afford the title compound (102.00 mg, 305.05 μmol,67.60% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 5.01 (s, 2H),4.67 (s, 2H), 4.05 (s, 2H), 3.73 (s, 2H), 3.20 (s, 3H), 2.76 (s, 2H),1.49 (s, 9H).

Intermediate 3: Tert-Butyl8-hydroxy-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxylate

To a solution of tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(60.00 mg, 179.44 μmol, 1.00 eq) (60.00 mg, 179.44 μmol, 1.00 eq) inMeOH (4.00 mL) was added NaBH₄ (13.58 mg, 358.88 μmol, 2.00 eq). Themixture was stirred at 15° C. for 1 h. The mixture was diluted withbrine (30 mL), extracted with EtOAc (30 mL*2) and DCM (30 mL). Theorganic phase was dried over Na₂SO₄, filtered and concentrated in vacuoto afford the title compound (51.00 mg, 136.45 μmol, 76.04% yield, 90%purity) as yellow solid, which was used directly for the next step.LCMS: 337 [M+1].

Intermediate 4: Tert-Butyl10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

Step 1. 5-tert-butyl 3-ethyl2-(3-((tert-butoxycarbonyl)amino)propyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate.To a solution of O5-tert-butyl O3-ethyl2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (500.00 mg,1.69 mmol, 1.00 eq) in THF (5.00 mL) was added tert-butylN-(3-bromopropyl)carbamate (482.91 mg, 2.03 mmol, 1.20 eq) followed byDBU (385.93 mg, 2.54 mmol, 382.11 μ μL, 1.50 eq). The mixture was heatedto 50° C. for 16 hr. TLC (PE:EA=1:1) showed the starting materialconsumed and two main spots appeared. The mixture was extracted withEtOAc (100 mL*2) and H₂O (50 mL). The combined organic layer was driedwith Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. Theresidue was purified by flash chromatography (PE:EA=20%50%) to affordthe title compound (400.00 mg, 875.06 mol, 51.78% yield, 99% purity) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ=4.97 (brs, 1H), 4.49-4.65 (m,4H), 4.34 (q, J=7.0 Hz, 2H), 3.69 (brs, 2H), 3.08 (d, J=5.9 Hz, 2H),2.74 (brs, 2H), 1.99 (quin, J=6.3 Hz, 2H), 1.49 (s, 9H), 1.44 (s, 9H),1.39 (t, J=7.2 Hz, 4H).

Step 2. ethyl2-(3-aminopropyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-carboxylate.To a solution of O5-tert-butyl O3-ethyl2-[3-(tert-butoxycarbonylamino)propyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate(400.00 mg, 883.90 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (6.16g, 54.02 mmol, 4.00 mL, 61.12 eq). The mixture was stirred at 10° C. for1 hr. The mixture was concentrated in vacuum to afford the titlecompound (430.00 mg, crude, as brown oil.

Step 3. tert-butyl11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of ethyl2-(3-aminopropyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylate(400.00 mg, 832.71 μmol, 1.00 eq, in EtOH (50.00 mL) was added K₂CO₃(460.35 mg, 3.33 mmol, 4.00 eq). The mixture was stirred at 70-80° C.for 32 hr. The mixture was cooled to 10° C. and Boc₂O (363.48 mg, 1.67mmol, 382.61 μ μL, 2.00 eq) was added. The mixture was stirred at 10° C.for 1 hr. TLC (DCM:MeOH=10:1) showed one main spot appeared. The mixturewas concentrated in vacuum. The residue was extracted with EtOAc (50mL*2) and H₂O (20 mL). The combined organic layer was dried over Na₂SO₄,filtrated. The filtrate was concentrated in vacuum. The residue waspurified by flash chromatography (DCM:MeOH:0%˜7%) to afford the titlecompound (155.00 mg, 505.94 μmol, 60.76% yield) as white solid.

Step 4. tert-butyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (100.00 mg, 326.41 μmol, 1.00 eq) inTHF (2.00 mL) was added NaH (19.58 mg, 489.61 mol, 60% purity, 1.50 eq).The mixture was stirred at 0° C. for 30 min. CH₃I (69.50 mg, 489.61μmol, 30.48 μL, 1.50 eq) was added. The mixture was stirred at 10° C.for 1 hr. LCMS showed one main peak with desired Ms detected. Themixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL*2).The combined organic layer was dried with Na₂SO₄, filtrated. Thefiltrates was concentrated in vacuum to afford the title compound (90.00mg, crude) as colorless oil.

Intermediate 5: Tert-Butyl11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

Step 1. 5-tert-butyl 3-ethyl2-[3-(tert-butoxycarbonylamino)propyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate.To a solution of O5-tert-butyl O3-ethyl2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (2.00 g,6.77 mmol, 1.00 eq) in THF (20.00 mL) was added tert-butylN-(3-bromopropyl)carbamate (1.93 g, 8.12 mmol, 1.20 eq), followed by DBU(1.55 g, 10.16 mmol, 1.53 mL, 1.50 eq), the reaction mixture was stirredat 50° C. for 16 hours. Several new peaks were shown on LCMS and about30% of desired product was detected. The reaction mixture was dilutedwith EtOAc (150 mL) and washed with water (50 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography to afford the title compound (1.70g, 3.76 mmol, 55.49% yield) as white solid. ¹H NMR (400 MHz, CDCl₃)δ=4.94 (brs, 1H) 4.54-4.85 (m, 4H) 4.30-4.35 (m, 2H) 3.67 (br s, 2H)3.06-3.08 (br d, J=5.90 Hz, 2H) 2.72 (br s, 2H) 1.94-2.01 (m, J=6.43 Hz,2H) 1.47 (s, 9H) 1.42 (s, 9H) 1.36-1.39 (t, J=7.15 Hz, 3H). LCMS: 453[M+1].

Step 2. ethyl2-(3-aminopropyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylate.To a solution of O5-tert-butyl O3-ethyl2-[3-(tert-butoxycarbonylamino)propyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate(1.70 g, 3.76 mmol, 1.00 eq) in dioxane (10.00 mL) was added HCl/dioxane(4 M, 20.00 mL, 21.28 eq). The reaction mixture was stirred at 20° C.for 2 hours. TLC indicated compound 3 was consumed completely, and onemajor new spot with larger polarity was detected. The solvent wasremoved on a rotary evaporator to afford the title compound (1.10 g,crude, as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.65-4.68 (t,J=6.65 Hz, 2H) 4.38-4.44 (m, 4H) 3.53-3.56 (t, J=6.27 Hz, 2H) 3.03-3.07(t, J=6.21 Hz, 2H) 2.94-2.98 (br t, J=7.65 Hz, 2H) 2.17-2.24 (m, 2H)1.39-1.42 (t, J=7.09 Hz, 3H)

Step 3. tert-butyl11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of ethyl2-(3-aminopropyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylate(900.00 mg, 2.77 mmol, 1.00 eq) in EtOH (10.00 mL) was added NaOMe(597.95 mg, 11.07 mmol, 4.00 eq) under N₂. The reaction mixture wasstirred at 20° C. for 3 hours. LCMS showed compound 4 was consumedcompletely. The solvent was removed on a rotary evaporator. To theresidue, was added THF (10.00 mL), followed by a solution of NaHCO₃(697.44 mg, 8.30 mmol, 322.89 μL, 3.00 eq) in H₂O (2.00 mL) and (Boc)₂O(905.94 mg, 4.15 mmol, 953.62 μL, 1.50 eq). The reaction mixture wasstirred at 20° C. for one hour. LCMS showed one main peak with desiredMS was detected. The reaction mixture was diluted with EtOAc (50 mL) andwashed with water (30 mL*2), the organic phase was dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bysilica gel chromatography to afford the title compound (600.00 mg, 1.96mmol, 70.70% yield) was obtained as white solid. LCMS: 329 [M+23].

Intermediate 6: Tert-Butyl 9-methyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b]pyrazine-2-carboxylate

Step 1. tert-butyl 3-[2-hydroxyethyl(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. To amixture of5-tert-butoxycarbonyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylicacid (1.00 g, 3.74 mmol, 1.00 eq) and 2-(methylamino)ethanol (1.41 g,18.71 mmol, 1.49 mL, 5.00 eq) in DMF (5.00 mL) was added HATU (2.13 g,5.61 mmol, 1.50 eq) and DIPEA (7.25 g, 56.12 mmol, 9.80 mL, 15.00 eq) inone portion under N₂. The mixture was stirred at 80° C. for 10 hours.LCMS and TLC (Dichloromethane: Methanol=10:1) showed the reaction wascompleted. The residue was poured into water (50 mL). The aqueous phasewas extracted with ethyl acetate (50 mL*2). The combined organic phasewas washed with brine (50 mL*2), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by silica gelchromatography (Petroleum ether/Ethyl acetate=1/1,Dichloromethane:Methanol=20:1) to afford the title compound (750.00 mg,2.31 mmol, 61.82% yield, 100% purity) as white solid. LCMS: 325 [M+1].

Step 2. tert-butyl 9-methyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b]pyrazine-2-carboxylate. To a mixture of tert-butyl3-[2-hydroxyethyl(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(100.00 mg, 308.29 μmol, 1.00 eq) in THE (3.00 mL) was addedtributylphosphane (81.09 mg, 400.78 μmol, 98.88 μL, 1.30 eq) and DIAD(81.04 mg, 400.78 μmol, 77.92 μL, 1.30 eq) under N₂. The mixture wasstirred at 80° C. for 4 hours. TLC (Dichloromethane:Methanol=10:1)showed the reaction was completed. The mixture was poured into water (10mL) and stirred for 2 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-TLC (Dichloromethane: Methanol=10:1) toafford the title compound (70.00 mg, 228.49 mol, 74.12% yield) as yellowsolid. LCMS: 307 [M+1].

Intermediate 7: 3-(methylamino)butan-1-ol

Step 1. N-(3-hydroxy-1-methyl-propyl)formamide. To a mixture of3-aminobutan-1-ol (5.00 g, 56.09 mmol, 1.00 eq) and ethyl acetate (9.88g, 112.18 mmol, 10.98 mL, 2.00 eq) in EtOH (30.00 mL) was added ethylformate (9.88 g, 112.18 mmol, 10.98 mL, 2.00 eq) in one portion underN₂. The mixture was stirred at 80° C. for 12 hours. TLC(dichloromethane: methanol=10:1) showed the reaction was completed. Themixture was concentrated in vacuum to afford the title compound (6.00 g,51.22 mmol, 91.31% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.17(s, 1H), 5.75-5.97 (m, 1H), 4.13-4.43 (m, 1H), 3.53-3.68 (m, 2H), 3.27(br s, 1H), 1.74-1.97 (m, 1H), 1.34-1.52 (m, 1H), 1.15-1.31 (m, 3H).

Step 2. 3-(methylamino)butan-1-ol. To a mixture ofN-(3-hydroxy-1-methyl-propyl)formamide (2.00 g, 17.07 mmol, 1.00 eq) inTHF (10.00 mL) was added LiAlH₄ (1.30 g, 34.14 mmol, 2.00 eq) in oneportion at −10° C. under N₂. The mixture was stirred at −10° C. for 30min, then heated to 20° C. and stirred for 12 hours, then heated to 80°C. and stirred for 3 hours. TLC (dichloromethane: methanol=10:1) showedthe reaction was completed. The mixture was quenched with 1.3 mL of H₂O,followed by 1.3 mL of NaOH (15%) and 3.9 mL of H₂O. The mixture wasdried with anhydrous MgSO₄, filtered and concentrated in vacuum toafford the title compound (1.20 g, 11.63 mmol, 68.15% yield) as yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 3.71-3.93 (m, 2H), 2.83 (ddd, J=3.30,6.39, 8.28 Hz, 1H), 2.43 (s, 3H), 1.66-1.74 (m, 1H), 1.53 (s, 1H), 1.15(d, J=6.36 Hz, 3H).

Intermediate 8: Tert-Butyl9,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2-carboxylate

Step 1. tert-butyl3-[(3-hydroxy-1-methyl-propyl)-methyl-carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.To a mixture of5-tert-butoxycarbonyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylicacid (500.00 mg, 1.87 mmol, 1.00 eq) and 3-(methylamino)butan-1-ol(Intermediate 7, 771.92 mg, 7.48 mmol, 4.00 eq) in DMF (5.00 mL) wasadded HATU (1.07 g, 2.81 mmol, 1.50 eq) and DIPEA (3.63 g, 28.06 mmol,4.90 mL, 15.00 eq) in one portion under N₂. The mixture was stirred at80° C. for 10 hours. LCMS and TLC (dichloromethane: methanol=10:1)showed Desired product was detected. The residue was poured into water(10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*2).The combined organic phase was washed with brine (10 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=1/1, dichloromethane: methanol=20:1) to afford the titlecompound (300.00 mg, 510.74 μmol, 27.31% yield, 60% purity) as yellowsolid. LCMS:353 [M+1].

Step 2. tert-butyl9,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2-carboxylate. To a mixture of tert-butyl3-[(3-hydroxy-1-methyl-propyl)-methyl-carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(300.00 mg, 851.23 μmol, 1.00 eq) in THF (10.00 mL) was addedtributylphosphane (223.89 mg, 1.11 mmol, 273.03 μL, 1.30 eq) and DIAD(223.77 mg, 1.11 mmol, 215.16 μL, 1.30 eq) in one portion under N₂. Themixture was stirred at 80° C. for 12 hours. LCMS and TLC(Dichloromethane: Methanol=10:1) showed the desired product wasdetected. The mixture was poured into water (10 mL) and stirred for 2min. The aqueous phase was extracted with ethyl acetate (10 mL*2). Thecombined organic phase was washed with brine (10 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by prep-HPLC(FA) to afford the title compound (66.00 mg, 197.36μmol, 23.19% yield) as yellow solid. LCMS: 335 [M+1].

Intermediate 9:2-tert-butyl8-methyl8-methoxy-9-methyl-10-oxo-1,3,4,7-tetrahydropyrido[2,3]pyrazolo[2,4-c]pyrazine-2,8-dicarboxylate

Step 1. tert-butyl3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.Na (7.78 g, 338.60 mmol, 8.02 mL, 10.00 eq) was added to MeOH (100.00mL) portionwise at 0° C., and the mixture was stirred at 15° C. for 0.5hr under N₂. Then N-methylhydroxylamine (8.48 g, 101.58 mmol, 3.00 eq,HCl) was added to the mixture and the mixture was stirred at 15° C. for0.5 hr under N₂. Then 5-tert-butyl 3-ethyl1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate(Intermediate 30, 10.00 g, 33.86 mmol, 1.00 eq) was added, the mixturewas stirred at 70° C. for 16 hr under N2 atmosphere. TLC (PE/EA-1/1)showed the starting material was consumed completely and a new spot wasdetected mainly. The mixture was poured into ice-water (300 mL) andstirred for 5 min. Then the mixture was concentrated to remove MeOH. Theaqueous phase was adjusted to pH=6 with HCl (1 N, aq) and then extractedwith ethyl acetate (100 mL×3). The combined organic phase was washedwith brine (300 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum to afford the title compound (8.00 g, 27.00 mmol,79.73% yield) as a yellow solid.

LCMS: 297 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.62 (brs, 2H) 3.70 (t,J=5.52 Hz, 2H) 3.31-3.58 (m, 3H) 2.74 (s, 2H) 1.48 (s, 9H).

Step 2. tert-butyl4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate.A mixture of tert-butyl3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (8.00 g, 27.00 mmol, 1.00 eq),3-bromooxetane (4.07 g, 29.70 mmol, 1.10 eq), TBAI (997.22 mg, 2.70mmol, 0.10 eq) and Cs₂CO₃ (13.19 g, 40.50 mmol, 1.50 eq) in DMF (80.00mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 70° C. for 3 hr under N2 atmosphere. TLC (DCM/MeOH=10/1)showed the starting material was consumed completely and the titlecompound was major. The mixture was poured into water (200 mL) andstirred for 5 min. The aqueous phase was extracted with ethyl acetate(100 mL×3). The combined organic phase was washed with brine (300 mL×2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by column chromatography (SiO₂, PE/EA=100/1 to 1/2)to afford the title compound (4.50 g, 12.39 mmol, 45.88% yield, 97%purity) as a yellow solid. LCMS: 353 [M+1]. ¹H NMR (400 MHz, CDCl₃CDCl₃)δ=4.62 (brs, 2H) 4.53 (brs, 2H) 4.32-4.42 (m, 1H) 3.57-3.88 (m, 4H) 3.29(br. s., 3H) 2.68-2.79 (m, 2H) 1.41-1.53 (m, 9H).

Step 3.10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylicacid. To a mixture of tert-butyl4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate(1.00 g, 2.84 mmol, 1.00 eq) and NMO (2.50 g, 21.30 mmol, 2.25 mL, 7.50eq) in MeCN (30.00 mL) was added TPAP (199.61 mg, 568.00 mol, 0.20 eq)in one portion at 0° C. under N₂. The mixture was stirred at 0° C. for 2hr. LCMS showed the reaction was completed. The mixture was concentratedin vacuum to afford the title compound (1.04 g, crude) as black brownsolid. LCMS: 367 [M+1].

Step 4. 2-tert-butyl 8-methyl8-methoxy-9-methyl-10-oxo-1,3,4,7-tetrahydropyrido[2,3]pyrazolo[2,4-c]pyrazine-2,8-dicarboxylate.To a mixture of10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylicacid (1.04 g crude, 2.84 mmol, 1.00 eq) and K₂CO₃ (1.18 g, 8.52 mmol,3.00 eq) in MeCN (20.00 mL) was added Mel (1.21 g, 8.52 mmol, 530.70 μL,3.00 eq) in one portion at 25° C. under N₂. The mixture was stirred at25° C. 12 hours. LCMS showed the reaction didn't react. The startingmaterial was recovered: the reaction mixture was neutralized with HCl (1N, aq) to pH=3, then extracted with ethyl acetate (20 mL×2). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedto dryness. The reaction was performed again. To the recovered startingmaterial and K₂CO₃ (1.18 g, 8.52 mmol, 3.00 eq) in MeCN (20.00 mL) wasadded Mel (1.21 g, 8.52 mmol, 530.70 μL, 3.00 eq) in one portion at 25°C. under N₂. The mixture was stirred at 25° C. for 12 hours. LCMS andTLC (EA/PE=2/1) showed the reaction was completed, 50% of the titlecompound was detected. The residue was poured into water (20 mL) andstirred for 2 min. The aqueous phase was extracted with ethyl acetate(20 mL×2). The combined organic phase was washed with brine (20 mL×2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (PE/EA=10/1, 2/1) tothe title compound (200.00 mg, 507.07 μmol, 17.85% yield, 100% purity)as yellow oil. LCMS: 395 [M+1]. ¹H NMR (400 MHz, CDCl₃) 4.64-4.80 (m,3H), 4.51-4.62 (m, 1H), 3.88 (s, 3H), 3.60-3.79 (m, 2H), 3.38 (s, 3H),3.05 (s, 3H), 2.78 (br. s., 2H), 1.49 (s, 9H).

Intermediate 10: Methyl9-methyl-O-oxo-1,2,3,4-tetrahydropyrido[2,3]pyrazolo[2,4-b]pyrazine-8-carboxylate

A mixture of2-tert-butyl8-methyl8-methoxy-9-methyl-10-oxo-1,3,4,7-tetrahydropyrido[2,3]pyrazolo[2,4-c]pyrazine-2,8-dicarboxylate (20.00 mg, 50.71μmol, 1.00 eq) in HCl/dioxane (4 M, 20.00 mL, 1577.60 eq) was stirred at20° C. for 2 hours. LCMS showed the reaction was completed. The residuewas concentrated in vacuum to afford the title compound as the HCl salt(15.15 mg, 50.71 μmol, 100.00% yield) as yellow solid. LCMS: 263 [M+1].

Intermediate 11: Tert-Butyl8-[methoxy(methyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

To a mixture of2-tert-butoxycarbonyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylicacid (500.00 mg, 1.37 mmol, 1.00 eq) and N-methoxymethanaminehydrochloride (534.52 mg, 5.48 mmol, 4.00 eq) in THF (10.00 mL) wasadded T₃P (1.74 g, 2.74 mmol, 1.63 mL, 50% purity, 2.00 eq) and TEA(2.08 g, 20.55 mmol, 2.85 mL, 15.00 eq) in one portion under N₂. Themixture was stirred at 30° C. for 12 hours. LCMS and TLC(Dichloromethane:Methanol=10:1) showed the reaction was completed. Themixture was poured into water (15 mL) and stirred for 2 min. The aqueousphase was extracted with ethyl acetate (20 mL*2). The combined organicphase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography (Dichloromethane:Methanol=50:1-20:1) to afford thetitle compound (510.00 mg, 1.24 mmol, 90.45% yield, 99% purity) as whitesolid.

LCMS[M+1]: 408.

Intermediate 12: Tert-Butyl(3R)-3-methyl-1-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

Step 1. 5-tert-butyl 3-ethyl(6R)-2-[3-(tert-butoxycarbonylamino)propyl]-6-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate.To a solution of 5-tert-butyl 3-ethyl(6R)-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (4.50 g, 14.55 mmol, 1.00 eq) in THF(50.00 mL) was added tert-butyl N-(3-bromopropyl)carbamate (4.16 g,17.46 mmol, 1.20 eq) followed by DBU (3.32 g, 21.83 mmol, 3.29 mL, 1.50eq). The mixture was heated to 60° C. for 16 hr. TLC (PE: EtOAc=1:1)showed the starting material consumed and two new main spots appeared.The mixture was extracted with EtOAc (200 mL*2) and H₂O (50 mL). Thecombined organic layer was dried with Na₂SO₄, filtrated. The filtratewas concentrated in vacuum. The residue was purified by flashchromatography (PE:EtOAc=20%50%) to afford the title compound (4.50 g,9.64 mmol, 66.29% yield) as colorless oil.

Step 2. ethyl(6R)-2-(3-aminopropyl)-6-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylate.5-tert-butyl 3-ethyl(6R)-2-[3-(tert-butoxycarbonylamino)propyl]-6-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate(4.50 g, 9.64 mmol, 1.00 eq) was dissolved in HCl/dioxane (4 M, 50.00mL, 20.75 eq). The mixture was stirred at 20° C. for 2 hr. LCMS showedone main peak with desired Ms detected. The mixture was concentrated invacuum to afford the title compound as the HCl salt (3.30 g, crude) aswhite solid.

Step 3. tert-butyl(3R)-3-methyl-11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of ethyl(6R)-2-(3-aminopropyl)-6-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylate (3.27 g, 9.64 mmol, 1.00 eq) inMeOH (4.00 mL) was added CH₃ONa (2.08 g, 38.55 mmol, 4.00 eq). Themixture was stirred at 20° C. for 2 hr. LCMS showed one main peak withdesired Ms detected. The mixture was concentrated in vacuum. The residuewas dissolved in THE (8.00 mL) and H₂O (4.00 mL). NaHCO₃ (1.62 g, 19.28mmol, 749.76 μL, 2.00 eq) and Boc₂O (2.52 g, 11.57 mmol, 2.66 mL, 1.20eq) was added. The mixture was stirred at 20° C. for 16 hr. TLC(PE:EtOAc=0:1) showed one main spot appeared. The mixture was dilutedwith saturated NH₄Cl (100 mL) and extracted with EtOAc (200 mL*2). Thecombined organic layer was dried over Na₂SO₄, filtrated. The filtratewas concentrated in vacuum. The residue was purified by columnchromatography (PE:EtOAc=50%100%) to afford the title compound (2.40 g,7.49 mmol, 77.71% yield) as white solid.

Intermediate 13: 2-(tert-butyl) 9-methyl11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,9-dicarboxylate

Step 1. 3-aminotetrahydrofuran-2-one. To a solution of2-amino-4-hydroxy-butanoic acid (5.50 g, 46.17 mmol, 1.00 eq) in H₂O(50.00 mL) was added HCl (12 M, 50.02 mL, 13.00 eq), the mixture wasstirred at 120° C. for 3 hr. TLC (Dichloromethane:Methanol=10:1) showedthe reactant consumed. The mixture was concentrated to give the residue,most of the solvent was removed azeotropically with ethanol. Followingcrystal formation the solution was cooled on ice. The resulting solidwas filtered and rinsed three times with cold ethanol (20 mL). Thefiltrate was concentrated and cooled, producing additional homoserinelactone. The process was repeated 2 more times to afford the titlecompound as the HCl salt (4.20 g, 30.53 mmol, ⁶⁶0.13% yield) as whitesolid. ¹H NMR (400 MHz, d₆-DMSO) δ 4.52-4.63 (m, 1H), 4.32-4.49 (m, 2H),2.68-2.84 (m, 1H), 2.31-2.46 (m, 1H).

Step 2. 2-amino-4-bromo-butanoic acid. A mixture of3-aminotetrahydrofuran-2-one (4.00 g, 29.08 mmol, 1.00 eq) in HBr(103.67 g, 615.00 mmol, 69.57 mL, 48% purity, 21.15 eq) was stirred at100° C. for 6 hr. TLC (Dichloromethane: Methanol=10:1) showed thereaction was completed. The mixture was filtered to give the solid whichwas washed with methyl tertiary-butyl ether (50 mL) to afford the titlecompound (6.30 g, 23.96 mmol, 82.40% yield, HBr) as red solid

Step 3. methyl 2-amino-4-bromo-butanoate. To a solution of2-amino-4-bromo-butanoic acid (6.30 g, 23.96 mmol, 1.00 eq, HBr) in MeOH(50.00 mL) was added SOCl₂ (5.70 g, 47.92 mmol, 3.48 mL, 2.00 eq) at 0°C., the mixture was stirred at 20° C. for 12 hr. TLC (Petroleum ether:Ethyl acetate=1:1) showed the reaction was completed. The mixture wasconcentrated in vacuum to afford the title compound (6.30 g, 22.75 mmol,94.94% yield, HBr) as the red solid ¹H NMR (400 MHz, DEUTERIUM OXIDE) δ4.34 (t, J=6.65 Hz, 1H), 3.84 (s, 3H), 3.54-3.68 (m, 2H), 2.58 (qd,J=6.53, 15.29 Hz, 1H), 2.29-2.47 (m, 1H).

Step 4. methyl 2-(benzyloxycarbonylamino)-4-bromo-butanoate. To asolution of methyl 2-amino-4-bromo-butanoate (6.30 g, 22.75 mmol, 1.00eq, HBr) in H₂O (50.00 mL) was added NaHCO₃ (4.78 g, 56.87 mmol, 2.21mL, 2.50 eq) and CbzCl (4.66 g, 27.30 mmol, 3.88 mL, 1.20 eq) at 0° C.,the mixture was stirred at 20° C. for 16 hr. TLC (Petroleum ether: Ethylacetate=1:1) showed the reaction was completed. The mixture wasextracted with ethyl acetate (200 mL*2), the organic layer was washedwith brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated invacuum. The crude was triturated with Petroleum ether (30 mL) to affordthe title compound (3.60 g, 10.79 mmol, 47.45% yield, 99% purity) aswhite solid.

Step 5. 5-tert-butyl 3-ethyl2-[3-(benzyloxycarbonylamino)-4-methoxy-4-oxo-butyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate.To a solution of 5-tert-butyl 3-ethyl2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (3.60 g,12.19 mmol, 1.00 eq) and methyl2-(benzyloxycarbonylamino)-4-bromo-butanoate (4.31 g, 13.04 mmol, 1.07eq) in THF (50.00 mL) was added DBU (5.57 g, 36.57 mmol, 5.51 mL, 3.00eq), the mixture was stirred at 20° C. for 16 hr. TLC (Petroleum ether:Ethyl acetate=1:1) showed the reaction was complete. The mixture waspoured into water (20 mL), extracted with Ethyl acetate (20 mL*2), theorganic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated in vacuum. The crude was purified by prep. TLC(Petroleum ether: Ethyl acetate=1:1) to afford the title compound (3.60g, 6.28 mmol, 51.52% yield, 95% purity) as colorless oil.

Step 6. 5-tert-butyl 3-ethyl2-(3-amino-4-methoxy-4-oxo-butyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate. To a solution of 5-tert-butyl 3-ethyl2-[3-(benzyloxycarbonylamino)-4-methoxy-4-oxo-butyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate(3.60 g, 6.61 mmol, 1.00 eq) in MeOH (40.00 mL) was added Pd/C (700.00mg, 6.61 mmol, 10% purity, 1.00 eq). The mixture was stirred under H₂(15 Psi) at 20° C. for 2 hr. LCMS showed the reaction completed. Themixture was filtered and concentrated in vacuo to afford the titlecompound (2.60 g, 6.33 mmol, 95.83% yield) as colorless oil.

Step 7.2-tert-butoxycarbonyl-11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylicacid. To a solution of 5-tert-butyl 3-ethyl2-(3-amino-4-methoxy-4-oxo-butyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate(2.60 g, 6.33 mmol, 1.00 eq) in MeOH (3.00 mL) was added NaOMe (631.72mg, 11.69 mmol, 3.00 eq). The mixture was stirred at 20° C. for 16 hr.LCMS showed the reaction complete. The solvent was evaporated to givethe residue which was poured into aqueous HCl (0.5 M, 50 mL), extractedwith DCM (30 mL*4), the organic layer was washed with brine (20 mL),dried over anhydrous Na₂SO₄ and concentrated in vacuum to afford thetitle compound (1.10 g, 3.14 mmol, 80.50% yield) as yellow solid.

Step 8. 2-tert-butyl 9-methyl11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylate. To a solution of2-tert-butoxycarbonyl-11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylic acid (1.10 g, 3.14 mmol,1.00 eq) in DMF (20.00 mL) was added K₂CO₃ (650.87 mg, 4.71 mmol, 1.50eq) and Mel (1.34 g, 9.42 mmol, 586.44 μL, 3.00 eq). The mixture wasstirred at 20° C. for 16 hr. LCMS showed the reaction was complete. Themixture was poured into water (100 mL), extracted with ethyl acetate (50mL*2), the combined organic layer was washed with brine (30 mL*2), driedover anhydrous Na₂SO₄ and concentrated in vacuum to afford the titlecompound (1.10 g, 3.02 mmol, 96.18% yield) as colorless oil.

Intermediate 14: 2-tert-butyl 8-ethyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate

Step 1. ethyl 2-[[tert-butoxycarbonyl(methyl)amino]methyl]prop-2-enoate.A mixture of tert-butyl N-methylcarbamate (200.00 mg, 1.52 mmol, 1.00eq) in THF (5.00 mL) was added NaH (91.20 mg, 2.28 mmol, 60% purity,1.50 eq) at 0° C. for 0.5 hr under N₂, then ethyl2-(bromomethyl)prop-2-enoate (352.10 mg, 1.82 mmol, 1.20 eq) was addedto the mixture dropwise at 0° C., and the mixture was stirred at 15° C.for 2 hr under N2 atmosphere. TLC (PE/EA=10/1) the starting material wasconsumed completely and two new spots appeared. The mixture was pouredinto ice-water (10 mL) and stirred for 5 min. The aqueous phase wasextracted with ethyl acetate (5 mL×3). The combined organic phase waswashed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 5/1) toafford the title compound (112.00 mg, 460.34 μmol, 30.29% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 6.28 (s, 1H), 5.55 (s, 1H),4.23 (q, J=7.1 Hz, 2H), 4.07 (br s, 2H), 2.88 (br s, 3H), 1.45 (br s,9H), 1.31 (br s, 3H).

Step 2. ethyl2-(methylaminomethyl)prop-2-enoate. A mixture of ethyl2-[[tert-butoxycarbonyl(methyl)amino]methyl]prop-2-enoate (112.00 mg,460.34 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (4 M,5.00 mL, 43.45 eq), and then the mixture was stirred at 15° C. for 0.5hour. TLC (PE/EA=10/1) showed the starting material was consumedcompletely, a new spot was major. The mixture was concentrated in vacuumto afford the title compound (82.50 mg, 459.25 μmol, 99.76% yield, HCl)as a white solid, which was used directly for the next step.

Step 3. tert-butyl 3-[2-ethoxycarbonylallyl (methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. Amixture of5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylicacid (80.00 mg, 299.31 μmol, 1.00 eq), ethyl 2-(methylaminomethyl)prop-2-enoate (59.14 mg, 329.24 μmol, 1.10 eq, HCl), T₃P (285.70 mg,897.93 μmol, 267.01 μL, 3.00 eq) and TEA (151.44 mg, 1.50 mmol, 207.45μL, 5.00 eq) in THF (3.00 mL) was degassed and purged with N₂ for 3times, and then the mixture was stirred at 15° C. for 16 hours under N2atmosphere. TLC (DCM/MeOH=10/1) the starting material was consumedcompletely and anew spot appeared. The mixture was poured into water (10mL) and stirred for 5 min. The aqueous phase was extracted with ethylacetate (5 mL×3). The combined organic phase was washed with brine (10mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.

The residue was purified by prep-TLC (DCM/MeOH=10/1) to afford the titlecompound (46.00 mg, 105.49 μmol, 35.24% yield, 90% purity) as a whitesolid. LCMS: 393 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 6.35 (s, 1H), 5.67 (brs, 1H), 4.63 (s, 4H), 4.18-4.30 (m, 2H), 3.71 (br s, 2H), 2.91-3.47 (m,3H), 2.74 (br t, J=5.4 Hz, 2H), 1.48 (s, 9H), 1.31 (t, J=7.2 Hz, 3H).

Step 4. tert-butyl8-ethyl10-methyl-1l-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b],[1,4]diazepine-2,8-dicarboxylate. A mixture oftert-butyl3-[2-ethoxycarbonylallyl(methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(36.00 mg, 91.73 μmol, 1.00 eq), DBU (6.98 mg, 45.87 μmol, 6.91 μL, 0.50eq) in MeCN (1.00 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 50° C. for 2 hour under N2 atmosphere.TLC (DCM/MeOH=20/1) showed starting material was consumed completely andthe title compound was major. The mixture were poured into water (5 mL)and stirred for 5 min. The aqueous phase was extracted with ethylacetate (3 mL×3). The combined organic phase was washed with brine (5mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-TLC (DCM/MeOH=20/1) to afford the titlecompound (20.00 mg, 50.96 μmol, 55.56% yield) as a white solid. LCMS:393 [M+1]

Intermediate 15: Tert-Butyl(3R)-3,10-dimethyl-8-methylene-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

Step 1. 5-tert-butyl 3-ethyl(6R)-2-[2-(chloromethyl)allyl]-6-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate.To a solution of 5-tert-butyl 3-ethyl(6R)-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (15.00 g, 48.49 mmol, 1.00 eq) in DMF(4.00 mL) was added Cs₂CO₃ (23.70 g, 72.73 mmol, 1.50 eq), followed by3-chloro-2-(chloromethyl)prop-1-ene (12.12 g, 96.97 mmol, 11.22 mL, 2.00eq). The mixture was heated to 50° C. for 16 hr. TLC (PE:EtOAc=4:1)showed four spots appeared. The mixture was diluted with H₂O (300 mL)and extracted with EtOAc (500 mL*2). The combined organic layer waswashed with H₂O (300 mL*3), dried over Na₂SO₄ and filtrated. Thefiltrate was concentrated in vacuum. The reissue was purified by flashchromatography (PE:EtOAc=0%˜30%) to afford the title compound (7.00 g,17.59 mmol, 36.28% yield) as colorless oil.

Step 2. tert-butyl(3R)-3,10-dimethyl-8-methylene-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate and by-product tert-butyl(6R)-6-methyl-2-[2-(methylaminomethyl)allyl]-3-(methylcarbamoyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of 5-tert-butyl 3-ethyl(6R)-2-[2-(chloromethyl)allyl]-6-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate(7.00 g, 17.59 mmol, 1.00 eq) in EtOH (28.00 mL) was added methanamine(54.63 g, 527.70 mmol, 120.00 mL, 30.00 eq, 30% EtOH solution). Themixture was heated to 80° C. for 16 hr in sealed tube. TLC (PE:EtOAc=1:1) showed that starting material consumed completely and two newspots formed mainly. The mixture was concerned and purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 1/1) toafford the title compound (3.00 g, 6.36 mmol, 36.15% yield, 80% purity)as yellow gum.

Intermediate 16: Tert-Butyl(3R)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

Step 1. tert-butyl(3R)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate,tert-butyl(3R)-8-hydroxy-3,8,10-trimethyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 17), and tert-butyl(3R)-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 18). To a solution of tert-butyl(3R)-3,10-dimethyl-8-methylene-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 15, 3.20 g, 9.24 mmol, 1.00 eq) in THF (50.00 mL) wasadded BH₃.DMS (10 M, 3.70 mL, 4.00 eq) at 0° C. under N₂. The mixturewas stirred at 20° C. for 2 h. TLC (PE: EtOAc=1:2, showed that startingmaterial consumed. A solution of NaOH (2.59 g, 64.68 mmol, 7.00 eq) inH₂O (10.00 mL) was added at −30° C. dropwise, then H₂O₂ (6.28 g, 55.44mmol, 5.32 mL, 30% purity, 6.00 eq) was added slowly. The mixture wasstirred at 20° C. for 16 h. LC-MS indicated that 8% of tert-butyl(3R)-3,10-dimethyl-8-methylene-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylatewas still remained and 54% of tert-butyl(3R)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylateand 17% of tert-butyl(3R)-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylatewere detected. The mixture was extracted with ethyl acetate (30 mL*3)and H₂O (20 mL). The combined organic layer was washed with brine (20mL*1), dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=50/1 to 1/5, Plate 1), followed by prep-TLC toafford tert-butyl(3R)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(2.00 g, 5.48 mmol, 59.27% yield, 99.8% purity) as off-white gum,tert-butyl(3R)-8-hydroxy-3,8,10-trimethyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(150.00 mg, 382.78 mol, 4.14% yield, 93% purity) as off-white gum andtert-butyl(3R)-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(250.00 mg, 645.74 mol, 6.99% yield, 90% purity) as off-white gum.

Intermediate 17:Tert-Butyl(3R)-8-hydroxy-3,8,10-trimethyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

Isolated from Intermediate 16 (150.00 mg, 382.78 μmol, 4.14% yield, 93%purity) as off-white gum.

Intermediate 18: Tert-Butyl(3R)-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

Isolated from Intermediate 16 (250.00 mg, 645.74 μmol, 6.99% yield, 90%purity) as off-white gum.

Intermediate 19: Ethyl 2-[(2,2-difluoroethylamino)methyl]prop-2-enoate

Step 1. tert-butyl N-(2,2-difluoroethyl)carbamate. To a mixture of2,2-difluoroethanamine (10.00 g, 123.37 mmol, 1.00 eq) and Et₃N (24.97g, 246.74 mmol, 34.21 mL, 2.00 eq) in DCM (100.00 mL) was added Boc₂O(29.62 g, 135.71 mmol, 31.18 mL, 1.10 eq), and the mixture was stirredat 25° C. for 16 h. TLC indicated no starting material and one major newspot with lower polarity was detected. The mixture was diluted with DCM(150 mL) and washed with brine (150 mL). The organic phase was driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column to afford the title compound (17.90 g,98.80 mmol, 80.08% yield) as colorless solid. ¹H NMR (400 MHz, CDCl₃) δ5.55-6.02 (m, 1H), 4.58-4.88 (m, 1H), 3.26-3.58 (m, 2H), 1.38 (s, 9H).

Step 2. ethyl 2-[[tert-butoxycarbonyl(2,2-difluoroethyl)amino]methyl]prop-2-enoate. To a solution oftert-butyl N-(2,2-difluoroethyl)carbamate (2.00 g, 11.04 mmol, 1.00 eq)in THF (30.00 mL) was added NaH (574.08 mg, 14.35 mmol, 60% purity, 1.30eq) at 0° C. under N₂, followed by ethyl 2-(bromomethyl)prop-2-enoate(3.20 g, 16.56 mmol, 1.50 eq) after 0.5 h, and the mixture was stirredat 25° C. for 16 h. LCMS showed desired product was detected mainly. Themixture was quenched with H₂O (100 mL) and extracted with EtOAc (100mL). The organic phase was concentrated in vacuo, which was purified bysilica gel column to afford the title compound (2.30 g, 7.14 mmol,64.64% yield, 91% purity) as colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 6.30-6.32 (m, 1H), 5.70-6.15 (m, 1H),5.30-5.60 (m, 1H), 4.14-4.27 (m, 4H), 3.55-3.59 (m, 2H), 1.44-1.48 (m,9H), 1.28-1.34 (m, 3H).

Step 3. ethyl 2-[(2,2-difluoroethylamino)methyl]prop-2-enoate. Asolution of ethyl 2-[[tert-butoxycarbonyl(2,2-difluoroethyl)amino]methyl] prop-2-enoate (600.00 mg, 2.05 mmol, 1.00 eq) in HCl/dioxane (4M, 6.00 mL, 11.71 eq) was stirred at 25° C. for 2 h. TLC showed nostarting material and one new major spot was detected. The mixture wasconcentrated in vacuo to afford the title compound as the HCl salt(469.00 mg, 2.04 mmol, 99.62% yield) as colorless solid. ¹H NMR (400MHz, CDCl₃) δ 10.08-10.26 (m, 1H), 6.60 (m, 1H), 6.31 (m, 2H), 4.24 (m,2H), 3.91-4.01 (m, 2H), 3.28-3.45 (m, 2H), 1.28 (t, J=7.2 Hz, 3H).

Intermediate 20: 2-tert-butyl 8-ethyl(3R)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate

Step 1. tert-butyl (6R)-3-[2,2-difluoroethyl(2-ethoxycarbonylallyl)carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.A mixture of ethyl 2-[(2,2-difluoroethylamino)methyl]prop-2-enoate(Intermediate 19, 456.54 mg, 1.99 mmol, 1.40 eq),(6R)-5-tert-butoxycarbonyl-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylicacid (400.00 mg, 1.42 mmol, 1.00 eq), T₃P (904.85 mg, 2.84 mmol, 845.66μL, 2.00 eq) and Et₃N (719.42 mg, 7.11 mmol, 985.51 μL, 5.00 eq) in THE(10.00 mL) was heated to 70° C. for 16 h. The mixture was diluted withEtOAc (60 mL) and washed with HCl (1 M, 60 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo, which waspurified by prep-HPLC (FA) to afford the title compound (165.00 mg,339.77 μmol, 23.93% yield, 94% purity) as colorless oil. LCMS: 457[M+1].

Step 2. 2-tert-butyl 8-ethyl(3R)-10-(2,2-difluoroethyl)-3-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate. To a solution oftert-butyl (6R)-3-[2,2-difluoroethyl(2-ethoxycarbonylallyl)carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(165.00 mg, 361.46 μmol, 1.00 eq) in MeCN (6.00 mL) was added DBU (27.51mg, 180.73 μmol, 27.24 μL, 0.50 eq), and the mixture was heated to 50°C. for 2 h. TLC showed no starting material and major desired product.The mixture was diluted with EtOAc (30 mL) and washed with brine (30mL). The organic phase was concentrated in vacuo, which was purified byprep-TLC to afford the title compound (103.00 mg, 218.87 μmol, 60.55%yield, 97% purity) as colorless oil. LCMS: 457 [M+1].

Intermediate 21:(2S,3R)-3-((tert-butyldiphenylsilyl)oxy)-2-((methylamino)methyl)pent-4-en-1-ol

Step 1. ethyl 3-[benzyl(methyl)amino]propanoate. To a solution ofN-methyl-1-phenyl-methanamine (50.00 g, 412.61 mmol, 53.19 mL, 1.00 eq)in EtOH (200.00 mL) was added ethyl prop-2-enoate (49.57 g, 495.13 mmol,53.88 mL, 1.20 eq) under N₂, the reaction mixture was stirred at 20° C.for 16 hours. TLC indicated N-methyl-1-phenyl-methanamine was consumedcompletely, and one major new spot with lower polarity was detected. Thereaction mixture was concentrated on a rotary evaporator to afford thetitle compound (87.00 g, crude) as yellow oil, used in next stepdirectly. ¹H NMR (400 MHz, CDCl₃) δ=7.21-7.35 (m, 5H), 4.15 (q, J=7.17Hz, 2H), 3.52 (s, 2H), 2.72-2.80 (m, 2H), 2.48-2.56 (m, 2H), 2.22 (s,3H), 1.26 (t, J=7.15 Hz, 3H).

Step 2. ethyl 3-[tert-butoxycarbonyl(methyl)amino]propanoate. To amixture of ethyl 3-[benzyl(methyl)amino]propanoate (33.00 g, 149.12mmol, 1.00 eq) and (BoC)₂O (32.55 g, 149.12 mmol, 34.26 mL, 1.00 eq) inEtOH (200.00 mL) was added Pd/C (3.50 g, 10% purity) under N₂, thesuspension was degassed under vacuum and purged with H₂ three times, themixture was stirred under H₂ (50 psi) at 40° C. for 16 hours. TLCindicated starting material was consumed completely and one major newspot with lower polarity was detected. The reaction mixture was filteredand the filtrate was concentrated. The residue was purified by flashsilica gel chromatography to afford the title compound (24.00 g, 103.77mmol, 69.59% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ=4.12 (q,J=7.15 Hz, 2H), 3.48 (brs, 2H), 2.85 (s, 3H), 2.52 (t, J=6.78 Hz, 2H),1.44 (s, 9H), 1.21-1.29 (m, 3H).

Step 3. ethyl2-[[tert-butoxycarbonyl(methyl)amino]methyl]-3-hydroxy-pent-4-enoate. Toa solution of ethyl 3-[tert-butoxycarbonyl(methyl)amino]propanoate(25.00 g, 108.09 mmol, 1.00 eq) in THF (200.00 mL) was added LDA (1 M,162.14 mL, 1.50 eq) dropwise at −78° C. under N₂, the reaction mixturewas stirred at −78° C. for 30 minutes, then a solution of prop-2-enal(7.88 g, 140.52 mmol, 9.38 mL, 1.30 eq) in THF (20.00 mL) was addeddropwise, and the reaction mixture was stirred at 25° C. for another 2hours. TLC indicated starting material was consumed completely andmultiple new spots formed. The reaction was added into aqueous solutionof NH₄Cl (200 mL) and then extracted with ethyl acetate (200 mL*2), thecombined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography to afford the title compound (18.00 g, 62.64 mmol, 57.95%yield) as yellow oil.

Step 4. ethyl2-[[tert-butoxycarbonyl(methyl)amino]methyl]-3-[tert-butyl(diphenyl)silyl]oxy-pent-4-enoate.To a mixture of ethyl2-[[tert-butoxycarbonyl(methyl)amino]methyl]-3-hydroxy-pent-4-enoate(25.50 g, 88.74 mmol, 1.00 eq) in DCM (200.00 mL) was added imidazole(6.65 g, 97.62 mmol, 1.10 eq), DMAP (1.08 g, 8.87 mmol, 0.10 eq) andTBDPSCl (26.83 g, 97.62 mmol, 25.08 mL, 1.10 eq) in one portion at 0° C.under N₂. The mixture was stirred at 30° C. for 12 hours. TLC showed 30%of starting material was remained. Then added TBDPSCl (24.39 g, 88.74mmol, 22.80 mL, 1.00 eq) and stirred at 30° C. for another 12 hours. TLCshowed the reaction completed. The mixture was poured into water (200mL). The aqueous phase was extracted with DCM (100 mL*2). The combinedorganic phase was washed with brine (100 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bysilica gel chromatography to afford the title compound (49.00 g, crude)as yellow oil.

Step 5. tert-butyl((2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pent-4-en-1-yl)(methyl)carbamateand tert-butyl((2S,3R)-3-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pent-4-en-1-yl)(methyl)carbamate.To a mixture of ethyl2-[[tert-butoxycarbonyl(methyl)amino]methyl]-3-[tert-butyl(diphenyl)silyl]oxy-pent-4-enoate (17.00 g, 32.33 mmol, 1.00 eq) in THE(200.00 mL) was added LiBH₄ (4.22 g, 193.98 mmol, 6.00 eq) in oneportion at 0° C. under N₂. The mixture was stirred at 30° C. for 60hours. TLC showed the reaction completed, and two spots were detected.The mixture was poured into water (300 mL). The aqueous phase wasextracted with DCM (100 mL*2). The combined organic phase was washedwith brine (50 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography to afford tert-butyl((2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pent-4-en-1-yl)(methyl)carbamate(3.88 g, 8.02 mmol, 24.81% yield) as yellow oil and tert-butyl((2S,3R)-3-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pent-4-en-1-yl)(methyl)carbamate(940.00 mg, 1.94 mmol, 6.01% yield) as yellow oil.

Step 6.(2S,3R)-3-((tert-butyldiphenylsilyl)oxy)-2-((methylamino)methyl)pent-4-en-1-ol.To a solution of tert-butyl((2S,3R)-3-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pent-4-en-1-yl)(methyl)carbamate(1.35 g, 2.79 mmol, 1.00 eq) in DCM (10.00 mL) was added TFA (7.70 g,67.53 mmol, 5.00 mL, 24.21 eq), the reaction mixture was stirred at 25°C. for 30 minutes. TLC indicated starting material was consumedcompletely. The reaction mixture was concentrated on a rotary evaporatorto afford the title compound (1.35 g, crude, TFA) as yellow oil, used innext step directly. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.62-7.71 (m, 4H),7.36-7.48 (m, 6H), 5.83 (ddd, J=7.34, 10.30, 17.33 Hz, 1H), 4.97-5.08(m, 2H), 4.22 (dd, J=4.89, 7.09 Hz, 1H), 3.82 (dd, J=3.55, 10.27 Hz,1H), 3.60 (t, J=9.90 Hz, 1H), 3.13-3.20 (m, 1H), 2.97-3.06 (m, 1H), 2.60(s, 3H), 2.04-2.14 (m, 1H), 1.07 (s, 9H).

Intermediate 22: Tert-Butyl(8Z)-11-methyl-12-oxo-3,4,7,10-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazocine-2-carboxylate

Step 1. 5-tert-butyl 3-ethyl 2-allyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate. To a solution of5-tert-butylO3-ethyl2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (20.00 g,67.72 mmol, 1.00 eq) and 3-bromoprop-1-ene (12.29 g, 101.58 mmol, 1.50eq) in DMF (200.00 mL) was added Cs₂CO₃ (55.16 g, 169.30 mmol, 2.50 eq).Then the mixture was stirred at 25° C. for 16 h. TLC (PE: EtOAc=3:1)showed that reactant 5-tert-butylO3-ethyl2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate was consumedcompletely and two new spots formed. The mixture was diluted with 100 mLof water and extracted with EtOAc (100 mL*3). The organic phase waswashed with brine (100 mL*1) and dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=50/1 to 3/1) toafford the title compound (13.50 g, 40.25 mmol, 59.44% yield) wasobtained as white solid.

Step 2.2-allyl-5-tert-butoxycarbonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxylicacid. To a solution of 5-tert-butyl 3-ethyl2-allyl-6,7-dihydro-4H-pyrazolo[4,3-c] pyridine-3,5-dicarboxylate(640.00 mg, 1.91 mmol, 1.00 eq) in THF (20.00 mL) and H₂O (4.00 mL) wasadded NaOH (152.65 mg, 3.82 mmol, 2.00 eq) at 25° C. Then the mixturewas heated to 50° C. for another 16 h. TLC (EtOAc:MeOH=10:1) showed thatreactant 5-tert-butyl 3-ethyl 2-allyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate remained and one new spot formed. Then 2 mLof MeOH was added and the resulting mixture was still stirred at 50° C.for 3 h. TLC (EtOAc: MeOH=10:1) showed that reactant 5-tert-butyl3-ethyl 2-allyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate was consumed completely and one main new spotformed. The mixture was diluted with 30 mL of water and concentrated invacuo to remove the organic solvent. Then the pH of the aqueous phasewas adjusted to 5 by adding HCl (3N). The aqueous phase was extractedwith EtOAc (30 mL*4), and the organic phase was washed with brine (30mL*1), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The title compound (590.00 mg, crude) was obtained as white solid.

Step 3. tert-butyl2-allyl-3-[allyl(methyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of2-allyl-5-tert-butoxycarbonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (590.00 mg, 1.92 mmol, 1.00 eq) and N-methylprop-2-en-1-amine(204.79 mg, 2.88 mmol, 273.06 μL, 1.50 eq) in DMF (10.00 mL) was addedPYBOP (1.10 g, 2.11 mmol, 1.10 eq), HOBt (285.33 mg, 2.11 mmol, 1.10 eq)and DIPEA (1.49 g, 11.52 mmol, 2.01 mL, 6.00 eq) with stirring at 25° C.for 1 h. TLC (PE:EtOAc=1:1) showed that reactant2-allyl-5-tert-butoxycarbonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxylic acid was consumed completely and one new spotformed. LCMS indicated that desired product was detected. The mixturewas diluted with 30 mL of water and extracted with EtOAc (30 mL*4). Theorganic phase was collected and washed with brine (20 mL*1), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=30/1 to 1/1) to afford the title compounds (650.00 mg, 1.80mmol, 93.76% yield) as colorless oil.

Step 4. tert-butyl(8Z)-11-methyl-12-oxo-3,4,7,10-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazocine-2-carboxylate.To a solution of tert-butyl2-allyl-3-[allyl(methyl)carbamoyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(275.00 mg, 762.94 μmol, 1.00 eq) in DCE (480.00 mL) was added[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium(95.61 mg, 152.59 mol, 0.20 eq) in one portion under N₂, Then themixture was stirred at 85° C. for 16 h. TLC (PE:EtOAc=1:3) showed thatreactant 5 still remained and two new spots formed. The mixture wasconcentrated in vacuo. The 600 mg of the residue combined with twobatches in parallel was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=50/1 to 1/3) to afford the title compound(180.00 mg, 541.52 mol, 35.49% yield) as yellow oil.

Intermediate 23: Tert-Butyl11-methyl-12-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazocine-2-carboxylate

To a solution of tert-butyl(8Z)-11-methyl-12-oxo-3,4,7,10-tetrahydro-H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazocine-2-carboxylate(Intermediate 22, 60.00 mg, 180.51 μmol, 1.00 eq) in MeOH (5.00 mL) wasadded Pd/C (50.00 mg, 10.00 μL, 10% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 2 hours. TLC (PE: EtOAc=1:3)showed that reactant 6 consumed completely and one main new spot formed.The mixture was diluted with 10 mL of MeOH, filtered and concentrated invacuo to afford the title compound (61.00 mg, crude) as yellow oil,which was directly used without further purification.

Intermediate 24: Tert-Butyl3′-hydroxy-10-methyl-11-oxo-spiro[3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8,1′-cyclobutane]-2-carboxylate

Step 1. [3-benzyloxy-1-(hydroxymethyl)cylcobutyl]methanol. To asuspension of LAH (1.55 g, 40.80 mmol, 2.50 eq) in THF (50.00 mL) wasadded a solution of diethyl 3-benzyloxycyclobutane-1,1-dicarboxylate(5.00 g, 16.32 mmol, 1.00 eq) in THF (20.00 mL) dropwise at −40° C. Theresulting suspension was stirred at 20° C. for 3 hr. TLC (PE:EtOAc=0:1)showed the starting material consumed and one main spot formed. Themixture was diluted with THF (300 mL) and quenched by H₂O (1.5 mL), 15%NaOH (1.5 mL) and H₂O (4.5 mL), filtrated. The filtrate was concentratedin vacuum to afford the title compound (3.30 g, crude) as white solid.

Step 2. 2-(benzyloxy)-6,8-dioxa-7-thiaspiro[3.5]nonane 7-oxide. To asolution of [3-benzyloxy-1-(hydroxymethyl)cyclobutyl]methanol (3.30 g,14.85 mmol, 1.00 eq) in DCM (90.00 mL) was added TEA (3.31 g, 32.67mmol, 4.53 mL, 2.20 eq) followed by SOCl₂ (2.12 g, 17.82 mmol, 1.29 mL,1.20 eq) at −10° C. The mixture was stirred at 0° C. for 1 hr. TLC(PE:EtOAc=1:1) showed the starting material consumed, TLC(PE:EtOAc=10:1) showed one main spot appeared. The mixture was dilutedwith H₂O (50 mL) and extracted with DCM (100 mL*2). The combined organiclayer was dried over Na₂SO₄, filtrated. The filtrate was concentrated invacuum. The residue was purified by column chromatography(PE:EtOAc=100:1) to afford the title compound (3.20 g, 11.93 mmol,80.31% yield) as colorless oil.

Step 3. 2-benzyloxy-6,8-dioxa-7thiaspiro[3.5]nonane 7,7-dioxide.2-benzyloxy-6,8-dioxa-7thiaspiro[3.5]nonane 7-oxide (2.50 g, 9.32 mmol,1.00 eq) was dissolved in H₂O (7.50 mL), MeCN (5.00 mL) and CCl₄ (5.00mL). RuCl₃H₂O (210.04 mg, 931.69 μmol, 0.10 eq) was added to themixture, followed by NaIO₄ (3.99 g, 18.63 mmol, 1.03 mL, 2.00 eq). Thereaction mixture was then stirred at 20° C. for 1 hr. TLC (PE:EtOAc=5:1)showed the starting material consumed and one main spot appeared. Themixture was diluted with saturated NaHCO₃ (80 mL) and extracted withEtOAc (200 mL*2). The combined organic layer was dried over Na₂SO₄,filtrated and concentrated in vacuum. The residue was purified by flashchromatography (PE:EtOAc=10% 30%) to afford the title compound (2.40 g,8.44 mmol, 90.57% yield) as white solid.

Step 4. [3-benzyloxy-1-(methylaminomethyl)cyclobutyl]methyl hydrogensulfate. To a solution of 2-benzyloxy-6,8-dioxa-7thiaspiro[3.5]nonane7,7-dioxide (1.00 g, 3.52 mmol, 1.00 eq) in MeCN (2.00 mL) was addedCH₃NH₂ (2 M in THF, 26.40 mL, 15.00 eq). The mixture was heated to 65°C. for 16 hr. Three peaks showed on LCMS and 40% desired productdetected. The mixture was concentrated in vacuum and the residue waswashed with methyl tert-butyl (50 mL) to afford the title compound (1.10g, crude) as white solid.

Step 5. tert-butylN-[[3-benzyloxy-1-(hydroxymethyl)cyclobutyl]methyl]-N-methyl-carbamate.To a solution of [3-benzyloxy-1-(methylaminomethyl)cyclobutyl]methylhydrogen sulfate (1.10 g, 3.49 mmol, 1.00 eq) in THF (5.00 mL) was addedH₂SO₄ (68.42 mg, 697.57 μmol, 37.18 μL, 0.20 eq). The mixture was heatedto 50° C. for 6 hr. LCMS showed the starting material remained. Themixture was stirred at 70° C. for another 32 hr. LCMS showed a littlestarting material remained. The pH of the mixture was adjust to 11 withsaturated NaHCO₃ and added Boc₂O (761.22 mg, 3.49 mmol, 801.29 μL, 1.00eq). The mixture was stirred at 20° C. for 30 min. TLC (PE:EtOAc=3:1)showed two main spots appeared. The mixture was diluted with H₂O (50 mL)and extracted with EtOAc (80 mL*2). The combined organic layer was driedover Na₂SO₄, filtrated and concentrated in vacuum. The residue waspurified by flash chromatography (PE:EtOAc:0%20%) to afford the titlecompound (519.00 mg, 1.38 mmol, 39.46% yield, 89% purity) as colorlessoil.

Step 6. (3-(benzyloxy)-1-((methylamino)methyl)cyclobutyl)methanol. To asolution of tert-butyl N-[[3-benzyloxy-1-(hydroxymethyl)cyclobutyl]methyl]-N-methyl-carbamate (519.00 mg, 1.55 mmol, 1.00 eq) in DCM (5.00mL) was added TFA (3.00 mL). The mixture was stirred at 20° C. for 0.5hr. TLC (PE:EtOAc=5:1) showed the starting material consumed. Themixture was concentrated in vacuum to afford the title compound (600.00mg, crude, TFA) as brown oil.

Step 7. tert-butyl 3-[[3-benzyloxy-1-(hydroxy methylcyclobutyl]methyl-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylicacid (400.00 mg, 1.50 mmol, 1.00 eq) and [3-benzyloxy-1-(methylaminomethyl)cyclobutyl]methanol (524.01 mg, 1.50 mmol, 1.00 eq, TFA) inDMF (5.00 mL) was added PYBOP (780.58 mg, 1.50 mmol, 1.00 eq), HOBt(202.68 mg, 1.50 mmol, 1.00 eq) followed by DIEA (969.30 mg, 7.50 mmol,1.31 mL, 5.00 eq). The mixture was stirred at 20° C. for 1 hr. LCMSshowed one main peak with desired Ms detected. The mixture was extractedwith EtOAc (80 mL*3) and H₂O (50 mL). The combined organic layer waswashed with H₂O (80 mL*2), 1N HCl (50 mL) and saturated NaHCO₃ (50 mL).The combined organic layer was dried over Na₂SO₄, filtrated andconcentrated in vacuum. The residue was purified by columnchromatography (PE:EtOAc=30%-50%) to afford the title compound (300.00mg, 433.36 μmol, 28.89% yield, 70% purity) as colorless oil.

Step 8.tert-butyl-3-[[3-benzyloxy-1-(methylsulfonyloxy-methyl)cyclobutyl]methyl-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of tert-butyl3-[[3-benzyloxy-1-(hydroxymethyl)cyclobutyl]methyl-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(200.00 mg, 288.90 μmol, 1.00 eq) in DCM (1.00 mL) was added pyridine(114.26 mg, 1.44 mmol, 116.59 μL, 5.00 eq) followed by MsCl (49.64 mg,433.35 μmol, 33.54 μL, 1.50 eq). The mixture was stirred at 20° C. for 2hr. TLC (PE:EtOAc=1:1) showed the starting material remained and two newmain spots appeared. Another batch of MsCl (49.64 mg, 433.35 μmol, 33.54μL, 1.50 eq) was added and the mixture was stirred at 20° C. for 1 hr.TLC (PE:EtOAc=1:1) showed a little starting material remained and twonew main spots appeared. The mixture was extracted with DCM (30 mL*2)and H₂O (20 mL). The combined organic layer was washed saturated Cu₂SO₄(20 mL*2), dried over Na₂SO₄, filtrated and concentrated in vacuum. Theresidue was purified by prep-TLC (PE:EtOAc=1:1) to afford the titlecompound (60.00 mg, 106.63 μmol, 36.91% yield) as colorless oil.

Step 9. tert-butyl3′-benzyloxy-10-methyl-11-oxo-spiro[3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8,1′-cyclobutane]-2-carboxylate.To a solution of tert-butyl3-[[3-benzyloxy-1-(methylsulfonyloxymethyl)cyclobutyl]methyl-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(60.00 mg, 106.63 μmol, 1.00 eq) in THF (1.00 mL) was added NaH (8.53mg, 213.27 μmol, 60% purity, 2.00 eq) at 0° C. The mixture was stirredat 0° C. for 0.5 hr. LCMS showed 22% of starting material remained. Themixture was stirred at 20° C. for another 2 hr. LCMS showed one mainpeak with desired Ms detected. The mixture was quenched by saturatedNH₄Cl (10 mL) and extracted with EtOAc (10 mL*2). The combined organiclayer was dried over Na₂SO₄, filtrated and concentrated in vacuum. Theresidue was purified by prep-TLC (PE:EtOAc=1:1) to afford the titlecompound (27.00 mg, 57.87 μmol, 54.27% yield) as colorless oil.

Step 10. tert-butyl3′-hydroxy-10-methyl-1-oxo-spiro[3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8,1′-cyclobutane]-2-carboxylate.To a solution of tert-butyl3′-benzyloxy-10-methyl-11-oxo-spiro[3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8,1′-cyclobutane]-2-carboxylate(27.00 mg, 57.87 μmol, 1.00 eq) in MeOH (10.00 mL) was added Pd—C(10%, 5mg) under N₂. The suspension was degassed under vacuum and purged withH₂ several times. The mixture was stirred under H₂ (20 psi) at 40° C.for 16 hours. LCMS showed one main peak with desired MS detected. Themixture was dilute with MeOH (30 mL), filtrated and concentrated invacuum to afford the title compound (30.00 mg, crude) as brown oil.

Intermediate 25: Methyl2-[tert-butyl(diphenyl)silyl]oxy-4-(methylamino)butanoate

Step 1. 4-(tert-butoxycarbonylamino)-2-hydroxy-butanoic acid. To asolution of 4-amino-2-hydroxy-butanoic acid (10.00 g, 83.95 mmol, 1.00eq) in H₂O (75.00 mL) was added K₂CO₃ (11.60 g, 83.95 mmol, 1.00 eq)followed by a solution of Boc₂O (18.32 g, 83.95 mmol, 19.29 mL, 1.00 eq)in dioxane (50.00 mL) dropwise at 0° C. The resulting solution wasstirred at 20° C. for 16 hr. TLC (PE:EtOAc=0:1) showed one main spotappeared. The mixture was diluted with H₂O (80 mL) and washed with 100ml DCM to remove the remained Boc₂O. The pH of the aqueous layer wasadjusted to 4-5 with 1N hydrochloric acid and the resulting solution wasextracted with 4×100 mL of ethyl acetate. The organic layers werecombined and concentrated under vacuum to afford the title compound(16.00 g, 72.98 mmol, 86.94% yield) as colorless oil.

Step 2. methyl 4-(tert-butoxycarbonylamino)-2-hydroxy-butanoate. To asolution of 4-(tert-butoxycarbonylamino)-2-hydroxy-butanoic acid (5.00g, 22.81 mmol, 1.00 eq) in DMF (50.00 mL) was added Cs₂CO₃ (8.92 g,27.37 mmol, 1.20 eq) and CH₃I (3.24 g, 22.81 mmol, 1.42 mL, 1.00 eq)dropwise at 0° C. The mixture was stirred at 20° C. for 2 hr. TLC(PE:EtOAc=1:1) showed the starting material consumed and one main spotappeared. The mixture was diluted with H₂O (100 mL) and extracted withEtOAc (200 mL*2). The combined organic layer was washed with H₂O (200mL*2), dried over Na₂SO₄, filtrated and concentrated in vacuum. Theresidue was purified by column chromatography (PE:EtOAc=30%-50%) toafford the title compound (5.50 g, crude) as colorless oil.

Step 3. methyl4-(tert-butoxycarbonylamino)-2-[tert-butyl(diphenyl)silyl]oxy-butanoate.To a solution of methyl 4-(tert-butoxycarbonylamino)-2-hydroxy-butanoate(5.00 g, 21.44 mmol, 1.00 eq) in DCM (50.00 mL) was added imidazole(2.19 g, 32.16 mmol, 1.50 eq) followed by TBDPSCl (5.89 g, 21.44 mmol,5.50 mL, 1.00 eq) and DMAP (261.88 mg, 2.14 mmol, 0.10 eq). The mixturewas stirred at 20° C. for 16 hr. TLC (PE:EtOAc=1:1) showed the startingmaterial remained and TLC (PE:EtOAc=10:1) showed two main spotsappeared. The mixture was diluted with H₂O (50 mL) and extracted withDCM (80 mL*3). The combined organic layer was washed with H₂O (20 mL*3),dried over Na₂SO₄, filtrated and concentrated in vacuum. The residue waspurified by flash chromatography (PE:EtOAc:0%˜10%) to afford the titlecompound (6.50 g, 13.78 mmol, 64.28% yield) as colorless oil.

Step 4. methyl4-(tert-butoxycarbonyl(methyl)aminol-2-[tert-butyl(diphenyl)silyl]oxy-butanoate.To a solution of methyl4-(tert-butoxycarbonylamino)-2-[tert-butyl(diphenyl)silyl]oxy-butanoate(4.40 g, 9.33 mmol, 1.00 eq) in DMF (50.00 mL) was added Ag₂O (10.81 g,46.65 mmol, 5.00 eq) followed by CH₃I (6.62 g, 46.65 mmol, 2.90 mL, 5.00eq). The mixture was stirred at 20° C. for 16 hr. TLC (PE:EtOAc=10:1)showed the starting material remained, additional Ag₂O (2.0 g) and CH₃I(3 mL) were added and the mixture was stirred at 20° C. for another 120hr. TLC (PE:EtOAc=10:1) showed a little starting material remained andtwo main spots appeared. The mixture was diluted with EtOAc (200 mL) andfiltrated. The filtrates was diluted with H₂O (100 mL) and separated outthe organic layer. The organic layer was washed with H₂O (200 mL*2),dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum.The residue was purified by flash chromatography (PE:EtOAc: 0% 10%) toafford the title compound (3.20 g, 6.59 mmol, 70.62% yield) as colorlessoil.

Step 5. methyl2-[tert-butyl(diphenyl)silyl]oxy-4-(methylamino)butanoate. To a solutionof methyl 4-[tert-butoxycarbonyl(methyl)amino]-2-[tert-butyl(diphenyl)silyl]oxy-butanoate (1.30 g, 2.68 mmol, 1.00 eq) in DCM (10.00 mL) wasadded TFA (5.00 mL) at 0° C. The mixture was stirred at 20° C. for 2 hr.TLC (PE:EtOAc=10:1) showed the starting consumed. The mixture wasconcentrated in vacuum to afford the title compound (2.80 g, crude, TFA)as brown oil.

Intermediate 26:2-(tert-butoxycarbonyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylicacid

Step 1. tert-butyl3-[[3-[tert-butyl(diphenyl)silyl]oxy-4-methoxy-4-oxo-butyl]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylicacid (800.00 mg, 2.99 mmol, 1.00 eq) and methyl2-[tert-butyl(diphenyl)silyl]oxy-4-(methylamino)butanoate (Intermediate25, 2.99 g, 5.98 mmol, 2.00 eq, TFA) in DMF (10.00 mL) was added PYBOP(1.71 g, 3.29 mmol, 1.10 eq), HOBt (444.41 mg, 3.29 mmol, 1.10 eq),followed by DIEA (1.93 g, 14.95 mmol, 2.61 mL, 5.00 eq). The mixture wasstirred at 20° C. for 2 hr. LCMS showed one main peak with desired MSdetected. The mixture was extracted with EtOAc (50 mL*3) and H₂O (50mL). The combined organic layer was washed H₂O (50 mL*3), 1N HCl (50 mL)and saturated NaHCO₃ (50 mL), dried over Na₂SO₄, filtrated andconcentrated in vacuum. The residue was re-purified by columnchromatography (PE:EtOAc: 20% 100%) to afford the title compound (1.60g, 2.52 mmol, 84.29% yield) as white solid.

Step 2. tert-butyl3-[(3-hydroxy-4-methoxy-4-oxo-butyl)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of tert-butyl3-[[3-[tert-butyl(diphenyl)silyl]oxy-4-methoxy-4-oxo-but-yl]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(1.40 g, 2.21 mmol, 1.00 eq) in THF (14.00 mL) was added TBAF (2 M, 2.21mL, 2.00 eq). The mixture was stirred at 20° C. for 1 hr. TLC(PE:EtOAc=1:2) showed the starting material consumed and two main spotsappeared. The mixture was extracted with DCM (50 mL*2) and H₂O (30 mL).The combined organic layer was washed with H₂O (30 mL*2), 1N HCl (30 mL)and saturated NaHCO₃ (30 mL), dried over Na₂SO₄, filtrated. The filtratewas concentrated in vacuum to afford the title compound (1.5 g crude) aswhite solid.

Step 3.tert-butyl3-[(4-methoxy-3-methylsulfonyloxy-4-oxo-butyl)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylateand tert-butyl3-[(4-methoxy-3-methylsulfonyloxy-4-oxo-butyl)-methyl-carbamoyl]-2-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of tert-butyl3-[(3-hydroxy-4-methoxy-4-oxo-butyl)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(150.00 mg, 378.37 μmol, 1.00 eq) in DCM (5.00 mL) was added Py (29.93mg, 378.37 μmol, 30.54 μL, 1.00 eq), followed by MsCl (43.34 mg, 378.37μmol, 29.28 μL, 1.00 eq). The mixture was stirred at 20° C. for 2 hr.TLC (PE:EtOAc=0:1) showed the starting material remained and two newspots appeared. Additional MsCl (43.34 mg, 378.37 μmol, 29.28 μL, 1.00eq) was added and the mixture was stirred at 20° C. for 1 hr. TLC(PE:EtOAc=0:1) showed the starting material consumed and two new spotsappeared. The mixture was extracted with DCM (20 mL*2) and H₂O (20 mL).The combined organic layer was washed saturated Cu₂SO₄ (10 mL*2), driedover Na₂SO₄, filtrated and concentrated in vacuum. The residue waspurified by prep-TLC (PE:EtOAc=0:1) to affordtert-butyl3-[(4-methoxy-3-methylsulfonyloxy-4-oxo-butyl)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(20.00 mg, 42.15 μmol, 11.14% yield) as white solid and tert-butyl3-[(4-methoxy-3-methylsulfonyloxy-4-oxo-butyl)-methyl-carbamoyl]-2-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(150.00 mg, 271.43 μmol, 71.74% yield) as white solid.

Step 4.2-(tert-butoxycarbonyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylicacid. To a solution of tert-butyl3-[(4-methoxy-3-methylsulfonyloxy-4-oxo-butyl)-methyl-carbamoyl]-2-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(150.00 mg, 271.43 μmol, 1.00 eq) in THF (3.00 mL) was added NaH (21.71mg, 542.87 μmol, 60% purity, 2.00 eq). The mixture was stirred at 0° C.for 0.5 hr. LCMS showed the starting material and2-(tert-butoxycarbonyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylicacid in one peak. The mixture was stirred at 20° C. for another 3 hr.LCMS showed a little starting material remained. Additional NaH (21.71mg, 542.87 μmol, 60% purity, 2.00 eq) was added and the mixture wasstirred at 20° C. for 16 h. LCMS showed 57% of2-(tert-butoxycarbonyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylicacid and 22% of an unknown compound. The mixture was diluted with H₂O (5mL) and concentrated in vacuum to afford a crude mixture of the titlecompound (116.00 mg, crude) as brown oil.

Intermediate 27: Tert-Butyl8-(1-hydroxyallyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

To a mixture of tert-butyl10-methyl-11-oxo-8-prop-2-enoyl-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(3.70 g, 9.88 mmol, 1.00 eq) in MeOH (100.00 mL) was added CeCl₃ (4.87g, 19.76 mmol, 1.24 mL, 2.00 eq) in one portion at 0° C. under N₂. Themixture was stirred at 0° C. for 15 min, then NaBH₄ (1.50 g, 39.52 mmol,4.00 eq) was added to the mixture. The mixture was heated to 30° C. andstirred for 2 hours. LCMS and TLC (Dichloromethane:Methanol=10:1) showedthe reaction was completed. The mixture was poured into water (20 mL)and concentrated in reduced pressure. The aqueous phase was extractedwith ethyl acetate (50 mL*3). The combined organic phase was washed withbrine (20 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by silica gel chromatography(Dichloromethane:Methanol=100/1-20:1) to afford the title compound (2.70g, 6.74 mmol, 68.24% yield, 94% purity) as yellow solid, Which wasseparated by SFC (Analytical method: IC-3S_3_5_40_3 ML Column: ChiralpakIC-3 100×4.6 mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂from 5% to 40% Flow rate: 3 mL/min Wavelength: 220 nm. Separationmethod: Instrument: SFC 80; Column: IC-10 um; Mobile phase: A for CO₂and B for MeOH (0.1% NH₃H₂O); Gradient: B 35%; Flow rate: 60 mL/min;Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm)to give four isomers: tert-butyl(S*)-8-((S*)-1-hydroxyallyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate:650 mg, tert-butyl(R*)-8-((S*)-1-hydroxyallyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate:640 mg, tert-butyl(S*)-8-((R*)-1-hydroxyallyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate:650 mg and tert-butyl(R*)-8-((R*)-1-hydroxyallyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate:650 mg.

* Pure but unknown stereoisomer.

Intermediate 28: Tert-Butyl8-(1-benzyloxy-3-hydroxy-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate

Step 1. tert-butyl8-(1-benzyloxyallyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl8-(1-hydroxyallyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 27, 1.00 g, 2.66 mmol, 1.00 eq) in THE (15.00 mL) wasadded NaH (425.60 mg, 10.64 mmol, 60% purity, 4.00 eq). The mixture wasstirred at 0° C. for 30 min, then BnBr (682.41 mg, 3.99 mmol, 473.90 μL,1.50 eq) was added. The mixture was stirred at 40° C. for 2 hr. TLC(PE:EtOAc=0:1) showed the starting material consumed and one new spotappeared. The mixture was quenched with H₂O (50 mL) and extracted withEtOAc (30 mL*3). The combined organic layer was dried over Na₂SO₄,filtrated and concentrated in vacuum. The residue was purified by columnchromatography (PE:EtOAc=2:1˜1:1) to afford the title compound (700.00mg, 1.47 mmol, 55.44% yield, 98.3% purity) as white solid.

Step 2. tert-butyl8-(1-benzyloxy-3-hydroxy-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl8-(1-benzyloxyallyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (350.00 mg,750.16 μmol, 1.00 eq) and chlororhodium triphenylphosphane (69.41 mg,75.02 μmol, 0.10 eq) in THE (8.00 mL) was added 1,3,2-benzodioxaborole(1 M, 3.75 mL, 5.00 eq) at 0° C. The mixture was stirred at 10° C. for 3hr. A solution of NaOH (210.04 mg, 5.25 mmol, 7.00 eq) in H₂O (4.00 mL)was added at −3° C. dropwise. Then H₂O₂ (2.38 g, 20.97 mmol, 2.02 mL,30% purity, 27.96 eq) was added slowly. The mixture was stirred at 25°C. for 2 hr. TLC (PE:EtOAc=0:1) showed the starting material consumedand one main spot appeared. The mixture was extracted with DCM (90 mL*3)and H₂O (20 mL). The organic layer was washed with 20% NaOH (80 mL*2),dried over Na₂SO₄, filtrated and concentrated in vacuum. The residue waspurified by column chromatography (PE:EtOAc:50%100% then toEtOAc:MeOH:10%) to afford the title compound (272.00 mg, 516.40 μmol,68.84% yield, 92% purity) as brown solid.

Intermediate 29: Racemic Tert-Butyl8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate

A mixture oftert-buty110-methyl-8-(methylsulfonyloxymethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(150.00 mg, 350.06 μmol, 1.00 eq), 2,2-difluoroethanamine (567.51 mg,7.00 mmol, 20.00 eq) in DMSO (5.00 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 88° C. for 16 hourunder N2 atmosphere. LCMS showed the starting material was consumedcompletely, desired product was major. The mixture was poured into water(20 mL) and extracted with EtOAc (10 mL*2). The combined organic phasewas washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 1:3) toafford the title compound (82.00 mg, 176.51 μmol, 50.42% yield, 89%purity) as a yellow solid. LCMS: 414 [M+1].

Intermediate 30: 5-tert-butyl3-ethyl 1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate

Step 1. tert-butyl3-(2-ethoxy-2-oxo-acetyl)-4-oxo-piperidine-1-carboxylate. To LiHMDS (1M, 652.44 mL, 1.30 eq) was added a solution of tert-butyl4-oxopiperidine-1-carboxylate (100.00 g, 501.88 mmol, 1.00 eq) in THF(1.00 L) dropwise at −78° C. under N₂. The reaction mixture was stirredat −78° C. for 30 minutes under N₂. Then diethyl oxalate (95.35 g,652.44 mmol, 1.30 eq) was added dropwise. After addition, the reactionmixture was warmed to 15° C. over a period of 30 minutes and stirred at15° C. for another 2 hours. TLC (PE/EA=3/1, Rf=0.2) showed the reactionwas completed. The reaction was quenched with saturated aqueous solutionof NH₄Cl (1.5 L) and then neutralized with diluted hydrochloric acid,the aqueous layer was extracted with EtOAc (800 mL×3). The combinedorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuum to afford the title compound (165.00 g, crude) as yellow oiland used directly for next step.

Step 2. 5-tert-butyl3-ethyl 1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate. A mixture of tert-butyl3-(2-ethoxy-2-oxo-acetyl)-4-oxo-piperidine-1-carboxylate (165.00 g,551.25 mmol, 1.00 eq) and NH₂NH₂.H₂O (35.71 g, 606.37 mmol, 1.10 eq) inAcOH (1.00 L) was degassed and purged with N₂ for 3 times. Then themixture was stirred at 80° C. for 1 hour under N2 atmosphere. TLC(PE/EA=1/1, Rf=0.4) and LCMS showed the reaction was completed. Themixture was concentrated under reduced pressure. The residue wasdissolved in EtOAc (800 mL) and washed with Na₂CO₃ (1 N, 1.2 L). Theaqueous phase was extracted with ethyl acetate (800 mL×2). The combinedorganic phase was washed with brine (1 L×2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum to afford the title compound(130.00 g, 440.19 mmol, 79.85% yield) as a yellow solid. LCMS: 296[M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.57-4.65 (m, 2H), 4.36 (d,J=7.03 Hz, 2H), 3.67-3.74 (m, 2H), 2.75 (t, J=5.65 Hz, 2H), 1.49 (s,9H), 1.36-1.40 (m, 3H).

Compound 001:N-(3-chloro-4-fluorophenyl)-10-methyl-8-methylene-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.10-methyl-8-methylene-3,4,7,8,9,10-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11(2H)-one.To a solution of tert-butyl10-methyl-8-methylene-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 1, 340.00 mg, 1.02 mmol, 1.00 eq) in DCM (2.00 mL) wasadded TFA (3.08 g, 27.01 mmol, 2.00 mL, 26.48 eq) under N₂ and themixture was stirred at 15° C. for 1 h. The mixture was concentrated invacuo to afford the title compound as the TFA salt (446.00 mg, crude),which was used directly for the next step.

Step 2:N-(3-chloro-4-fluorophenyl)-10-methyl-8-methylene-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

A mixture of10-methyl-8-methylene-1,2,3,4,7,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (446.00 mg, 515.16 μmol, 1.00 eq, TFA), Et₃N(260.65 mg, 2.58 mmol, 357.05 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl) carbamate (136.86 mg, 515.16 μmol, 1.00 eq)in DCM (3.00 mL) was stirred at 10° C. for 16 h. The mixture was dilutedwith DCM (30 mL) and washed with HCl (1 M, 30 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo to give yellowoil. The oil was purified by silica gel column and prep-HPLC (FA) toafford the title compound (39.00 mg, 96.28 mol, 18.69% yield, 99.7%purity) as a white solid. LCMS: 404/406 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ7.60 (dd, J=2.69, 6.48 Hz, 1H), 7.18-7.23 (m, 1H), 7.03-7.11 (m, 1H),6.55 (s, 1H), 5.18 (d, J=10.39 Hz, 2H), 5.02 (s, 2H), 4.70 (s, 2H), 3.98(s, 2H), 3.87 (t, J=5.75 Hz, 2H), 3.19 (s, 3H), 2.86 (t, J=5.81 Hz, 2H).

Compound 002:N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

To a solution ofN-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylene-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(Compound 001; 50.00 mg, 123.81 mol, 1.00 eq) and chlororhodiumtriphenylphosphane (4.58 mg, 4.95 μmol, 0.04 eq) in THF (3.00 mL) wasadded 1,3,2-benzodioxaborole (1 M, 371.43 μL, 3.00 eq) at 0° C. underN₂. The mixture was stirred at 0° C. for 3 hr. TLC (DCM: MeOH=15:1)showed the starting material was consumed completely nearly. A solutionof NaOH (34.67 mg, 866.67 μmol, 7.00 eq) in H₂O (1.50 mL) was added at−30° C. dropwise. Then H₂O₂ (393.01 mg, 3.47 mmol, 333.06 μL, 30%purity, 28.00 eq) was added slowly. The mixture was stirred at 10° C.for 16 hr. LCMS showed the starting material/desire product=1/3. Themixture was quenched with saturated NaHSO₃ (50 mL) and extracted withEtOAc (50 mL). The organic phase was washed with NaOH (15%, 30 mL*3) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo togive brown oil. The oil was purified by prep-HPLC(FA) to afford thetitle compound (10.00 mg, 23.49 μmol, 18.97% yield, 99.1% purity) aswhite solid. LCMS: 422/424 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd,J=2.63, 6.54 Hz, 1H), 7.14-7.24 (m, 1H), 7.00-7.11 (m, 1H), 6.52 (s,1H), 4.67 (s, 2H), 4.41 (dd, J=7.09, 14.31 Hz, 1H), 4.20 (dd, J=5.56,14.24 Hz, 1H), 3.77-3.94 (m, 2H), 3.62-3.77 (m, 2H), 3.43-3.54 (m, 1H),3.32-3.43 (m, 1H), 3.19 (s, 3H), 2.84 (t, J=5.75 Hz, 2H), 2.61-2.77 (m,1H), 1.75 (br. s, 1H).

Compound 003:N-(3-chloro-4-fluorophenyl)-8-hydroxy-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.10-methyl-8-methylene-3,4,7,8,9,10-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11(2H)-oneTo a solution of tert-butyl10-methyl-8-methylene-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 1, 312.00 mg, 938.63 μmol, 1.00 eq) in DCM (3.00 mL) wasadded TFA (4.62 g, 40.52 mmol, 3.00 mL, 43.17 eq) under N₂ and themixture was stirred at 15° C. for 1 h. The mixture was concentrated invacuo to afford the title compound (325.00 mg, crude, TFA) as yellowoil, which was used directly for the next step.

Step 2.N-(3-chloro-4-fluorophenyl)-10-methyl-8-methylene-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamideA mixture of10-methyl-8-methylene-1,2,3,4,7,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (325.00 mg, 938.49 μmol, 1.00 eq, TFA), Et₃N(474.83 mg, 4.69 mmol, 650.45 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (249.33 mg, 938.49 μmol, 1.00 eq)in DCM (5.00 mL) was stirred at 10° C. for 16 h. LCMS indicated thestarting material/desired product=2/1. The mixture was heated to 30° C.for another 16 h. LCMS indicated the starting material/desiredproduct=1/2. The mixture was heated to 40° C. for another 16 h. TLC(DCM/MeOH=8/1) indicated the starting material was consumed completely.The mixture was diluted with DCM (60 mL) and washed with HCl (1 M, 60mL). The organic phase was dried over Na₂SO₄, filtered and concentratedin vacuo to give yellow oil. The oil was purified by silica gel columnto afford the title compound (320.00 mg, 792.39 μmol, 84.43% yield) asyellow solid. LCMS: 404/406 [M+1].

Step 3.N-(3-chloro-4-fluorophenyl)-8-hydroxy-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution ofN-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylene-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(50.00 mg, 123.81 μmol, 1.00 eq) in acetone (3.00 mL) and H₂O (1.50 mL)was added K₂OsO₄.2H₂O (2.28 mg, 6.19 μmol, 0.05 eq) and NMO (58.02 mg,495.24 μmol, 52.27 μL, 4.00 eq) at 0° C. The mixture was stirred at 10°C. for 16 h. The mixture was quenched with saturated NaHSO₃ (40 mL) andextracted with EtOAc (40 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to give black oil. The oil waspurified by prep-HPLC(FA) to afford the title compound (26.00 mg, 59.38μmol, 47.96% yield, 100% purity) as white solid. ¹H NMR (400 MHz, CDCl₃)δ 7.57 (dd, J=2.69, 6.48 Hz, 1H), 7.14-7.22 (m, 1H), 7.02-7.10 (m, 1H),6.56 (s, 1H), 4.67 (d, J=4.52 Hz, 2H), 4.31-4.41 (m, 1H), 4.18-4.29 (m,1H), 3.84 (d, J=7.95 Hz, 2H), 3.67-3.74 (m, 1H), 3.58-3.66 (m, 1H),3.34-3.45 (m, 1H), 3.26-3.34 (m, 1H), 3.22 (s, 3H), 3.02 (br. s., 1H),2.83 (t, J=5.81 Hz, 2H), 2.32-2.50 (m, 1H). LCMS: 438/440 [M+1].

Compound 004:N-(3-chloro-4-fluorophenyl)-8-hydroxy-10-methyl-1l-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. 8-hydroxy-10-methyl-2,3,4,7,8,9-hexahydro-H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one. To a solution of tert-butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (Intermediate 3, 49.00mg, 145.66 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g, 27.01mmol, 2.00 mL, 185.45 eq) and the mixture was stirred at 15° C. under N₂for 1 h. LCMS indicated the starting material was consumed completely.The mixture was concentrated in vacuo to afford desired product (51.00mg, 145.59 mol, 99.95% yield, TFA) as yellow oil, which was useddirectly for the next step.

Step 2.N-(3-chloro-4-fluorophenyl)-8-hydroxy-10-methyl-1l-oxo-1,3,4,7,8,9,1011-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of8-hydroxy-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (51.00 mg, 145.59 μmol, 1.00 eq, TFA), Et₃N(73.66 mg, 727.95 mol, 100.90 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl) carbamate (38.68 mg, 145.59 μmol, 1.00 eq)in DCM (4.00 mL) was stirred at 10° C. for 16 h. The mixture was dilutedwith DCM (40 mL) and washed with HCl (1M, 40 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo to give yellowoil. The oil was purified by prep-HPLC (FA) to afford the title compound(35.00 mg, 84.10 μmol, 57.77% yield, 98% purity) as white solid. ¹H NMR(400 MHz, CDCl₃) δ 7.58 (dd, J=2.63, 6.54 Hz, 1H), 7.15-7.22 (m, 1H),7.02-7.10 (m, 1H), 6.51 (s, 1H), 4.68 (d, J=2.69 Hz, 2H), 4.53-4.64 (m,2H), 4.26 (d, J=9.17 Hz, 1H), 3.85 (t, J=5.81 Hz, 2H), 3.59 (dd, J=4.10,15.22 Hz, 1H), 3.35 (dd, J=5.44, 15.22 Hz, 1H), 3.22 (s, 3H), 2.85 (t,J=5.75 Hz, 2H), 2.10 (br. s., 1H). LCMS: 408/410 [M+1].

Compound 005:N-(3-chloro-4-fluorophenyl)-8,8-difluoro-10-methyl-1l-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8,8-difluoro-10-methyl-1-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxylateTo a solution of tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (Intermediate 2, 80.00mg, 239.26 mol, 1.00 eq) in DCM (4.00 mL) was added DAST (115.70 mg,717.78 μmol, 94.84 μL, 3.00 eq) at −30° C. The mixture was stirred at15° C. for 16 h. The mixture was diluted with brine (30 mL), extractedwith DCM (30 mL*2). The organic phase was dried over Na₂SO₄, filteredand concentrated in vacuo to give yellow oil. The oil was purified byprep-TLC to afford the title compound (60.00 mg, 153.21 μmol, 64.04%yield, 91% purity) as yellow solid. LCMS: 379[M+23].

Step 2.8,8-difluoro-10-methyl-3,4,7,8,9,10-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11(2H)-one.To a solution of tert-butyl8,8-difluoro-10-methyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(60.00 mg, 168.36 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g,27.01 mmol, 2.00 mL, 160.45 eq) and the mixture was stirred at 15° C.under N₂ for 1 h. The mixture was concentrated in vacuo to afford thetitle compounded (62.00 mg, 150.70 mol, 89.51% yield, 90% purity, TFA)as yellow oil, which was used directly for the next step. LCMS: 257[M+1].

Step 3.N-(3-chloro-4-fluorophenyl)-8,8-difluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamideA mixture of8,8-difluoro-10-methyl-1,2,3,4,7,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (62.00 mg, 167.45 μmol, 1.00 eq, TFA), Et₃N(84.72 mg, 837.23 mol, 116.05 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl) carbamate (44.49 mg, 167.45 μmol, 1.00 eq)in DCM (4.00 mL) was stirred at 15° C. for 16 h. The mixture was dilutedwith DCM (40 mL) and washed with HCl (1 M, 40 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo to give yellowoil. The oil was purified by prep-HPLC (FA) to afford the title compound(37.00 mg, 86.31 μmol, 51.55% yield, 99.8% purity) as white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.58 (dd, J=2.57, 6.48 Hz, 1H), 7.16-7.24 (m,1H), 7.03-7.12 (m, 1H), 6.46 (s, 1H), 4.60-4.80 (m, 4H), 3.86 (t, J=5.75Hz, 2H), 3.72 (t, J=12.29 Hz, 2H), 3.25 (s, 3H), 2.88 (t, J=5.81 Hz,2H). LCMS: 428/430[M+1].

Compound 006:N-(3-chloro-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-fluoro-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxylate.To a solution of tert-butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 3, 80.00 mg, 237.82 μmol, 1.00 eq) in DCM (4.00 mL) wasadded DAST (153.34 mg, 951.28 μmol, 125.69 μL, 4.00 eq) at −30° C. Themixture was stirred at 15° C. for 16 h. TLC indicated the startingmaterial was consumed completely and one major new spot with lowerpolarity was detected. The mixture was diluted with brine (30 mL),extracted with DCM (30 mL*2). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to give yellow oil. The oil waspurified by prep-TLC to afford the title compound (56.00 mg, 162.18μmol, 68.20% yield, 98% purity) as yellow solid. LCMS: 361[M+23].

Step 2.8-fluoro-10-methyl-3,4,7,8,9,10-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11(2H)-one.To a solution of tert-butyl8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (56.00 mg, 165.49 μmol,1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL,81.61 eq) and the mixture was stirred at 15° C. under N₂ for 1 h. TLCshowed the reactant was consumed completely and one major new spot withlarger polarity was detected. The mixture was concentrated in vacuo toafford8-fluoro-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(59.00 mg, 150.73 μmol, 91.08% yield, 90% purity, TFA) as yellow oil,which was used directly for the next step. LCMS: 239 [M+1].

Step 3.N-(3-chloro-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.A mixture of 8-fluoro-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo [2,4-b][1,4]diazepin-11-one (59.00 mg, 167.48 μmol, 1.00eq, TFA), Et₃N (84.74 mg, 837.40 μmol, 116.08 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl) carbamate (44.49 mg, 167.48 μmol, 1.00 eq)in DCM (4.00 mL) was stirred at 15° C. for 16 h. The mixture was dilutedwith DCM (30 mL) and washed with HCl (1M, 30 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo to give yellowoil, which was purified by prep-HPLC(FA) to afford the title compound(41.00 mg, 99.04 μmol, 59.14% yield, 99% purity) as white solid. LCMS[M+1]: 410. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (dd, J=2.63, 6.54 Hz, 1H),7.17-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.63 (s, 1H), 4.64-4.85 (m, 2H),4.34-4.62 (m, 4H), 3.95-4.08 (m, 1H), 3.86 (q, J=5.42 Hz, 2H), 3.22 (s,3H), 2.87 (br t, J=5.69 Hz, 2H).

Compounds 007, 008, 009, 010, 011, 012, and 013 were prepared in manneranalogous to Compound 006.

Compound 007:N-(3-bromo-4-fluorophenyl)-8-fluoro-10-methyl-1l-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

LCMS [M+1]: 454. ¹H NMR (400 MHz, CDCl₃) δ=7.71-7.73 (m, 1H) 7.27-7.29(m, 1H) 7.04 (t, J=8.4 Hz, 1H) 6.71 (s, 1H) 4.66-4.81 (m, 2H) 4.38-4.52(m, 4H) 3.87-3.89 (m, 1H) 3.83-3.86 (m, 2H) 3.21 (s, 3H) 2.85-2.88 (m,2H)

Compound 008:N-(2-bromo-3-fluoropyridin-4-yl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

LCMS [M+1]: 455. ¹H NMR (400 MHz, CDCl₃) δ=8.15 (t, J=5.4 Hz, 1H) 8.06(d, J=5.6 Hz, 1H) 7.06-7.07 (m, 1H) 4.79-4.87 (m, 2H) 4.37-4.51 (m, 4H)3.87-3.89 (m, 1H) 3.84-3.86 (m, 2H) 3.21 (s, 3H) 2.90 (t, J=5.6 Hz, 2H).

Compound 009:N-(3-cyano-4-fluorophenyl)-8-fluoro-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

LCMS [M+1]: 401. ¹H NMR (400 MHz, CDCl₃) δ=7.77-7.80 (m, 1H) 7.61-7.62(m, 1H) 7.13 (t, J=8.6 Hz, 1H) 6.99 (s, 1H) 4.82 (d, J=16 Hz, 1H) 4.68(d, J=15.6 Hz, 1H) 4.46-4.51 (m, 4H) 3.81-3.90 (m, 2H) 3.21 (s, 3H)2.85-2.88 (m, 2H).

Compound 010:8-fluoro-N-(4-fluoro-3-methylphenyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

LCMS [M+1]: 390. H NMR (400 MHz, CDCl₃) δ=7.24-7.25 (m, 1H) 7.10-7.13(m, 1H) 6.92 (t, J=9.0 Hz, 1H) 4.67-4.80 (m, 2H) 4.38-4.52 (m, 4H)3.86-3.87 (m, 1H) 3.84-3.85 (m, 1H) 3.21 (s, 3H) 2.85-2.88 (m, 2H) 2.25(s, 3H).

Compound 011:8-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

LCMS [M+1]: 444. ¹H NMR (400 MHz, CDCl₃) δ=7.68-7.70 (m, 1H) 7.59-7.61(m, 1H) 7.13 (t, J=9.4 Hz, 1H) 6.8 (s, 1H) 4.82 (d, J=15.6 Hz, 1H) 4.70(d, J=16 Hz, 1H) 4.39-4.52 (m, 4H) 3.90-3.92 (m, 1H) 3.84-3.89 (m, 2H)3.22 (s, 3H) 2.87 (t, J=5.4 Hz, 2H).

Compound 012:N-(5-chloro-2,4-difluorophenyl)-8-fluoro-10-methyl-1l-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

LCMS [M+1]: 428. ¹H NMR (400 MHz, CDCl₃) δ=8.17 (t, J=8.0 Hz, 1H) 6.95(t, J=5.6 Hz, 1H) 6.6 (s, 1H) 4.75-4.83 (m, 2H) 4.46-4.50 (m, 4H)3.90-4.00 (m, 1H) 3.83-3.89 (m, 2H) 3.21 (s, 3H) 2.87-2.90 (m, 2H).

Compound 013:N-(5-bromo-2,4-difluorophenyl)-8-fluoro-10-methyl-1l-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

LCMS [M+1]: 472. ¹H NMR (400 MHz, CDCl₃) δ=8.31 (t, J=7.8 Hz, 1H)6.91-6.96 (m, 1H) 6.61 (s, 1H) 4.71-4.83 (m, 2H) 4.46-4.51 (m, 4H)3.87-3.88 (m, 1H) 3.84-3.86 (m, 2H) 3.21 (s, 3H) 2.88 (t, J=5.6 Hz, 2H).

Compound 014:N-(3-chloro-4-fluoro-phenyl)-8,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide

Step 1. tert-butyl3-[methyl-[2-(methylsulfonyloxymethyl)allyl]carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of tert-butyl3-[2-(hydroxymethyl)allyl-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(100.00 mg, 285.38 μmol, 1.00 eq) and Et₃N (57.76 mg, 570.76 μmol, 79.12μL, 2.00 eq) in DCM (3.00 mL) was added a solution of MsCl (49.04 mg,428.07 μmol, 33.14 μL, 1.50 eq) in DCM (1.00 mL) at 0° C. under N₂ andthe mixture was stirred for another 1 h. The mixture was diluted withEtOAc (40 mL) and washed with brine (30 mL*2). The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo to afford thetitle compound (120.00 mg, crude), which was used directly for the nextstep.

Step 2. tert-butyl8,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(9H)-carboxylateand tert-butyl8,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxylate. To a solution oftert-butyl3-[methyl-[2-(methylsulfonyloxymethyl)allyl]carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(40.00 mg, 93.35 μmol, 1.00 eq) in DMF (2.00 mL) was added t-BuOK (15.71mg, 140.03 μmol, 1.50 eq) and the mixture was stirred at 50° C. for 16h. TLC showed the starting material was consumed completely and onemajor new spot with larger polarity was detected. LCMS indicated twopeaks with desired Ms. The mixture was diluted with EtOAc (30 mL) andwashed with HCl (1 M, 30 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to give oil. The oil was purified byprep-HPLC (FA) to afford tert-butyl8,10-dimethyl-11-oxo-1,3,4,7-tetrahydropyrido [2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (8.00 mg, 24.07 mol, 25.78% yield).¹H NMR (400 MHz, CDCl₃) δ 5.89 (s, 1H), 4.63-4.65 (m, 4H), 3.70 (s, 2H),3.22 (s, 3H), 2.73 (s, 2H), 1.94 (s, 3H), 1.48 (s, 9H) and tert-butyl8,10-dimethyl-11-oxo-1,3,4,9-tetrahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(8.00 mg, 24.07 μmol, 25.78% yield) (8.00 mg). ¹H NMR (400 MHz, CDCl₃) δ5.91 (s, 1H), 4.64-4.66 (m, 4H), 3.72 (s, 2H), 3.24 (s, 3H), 2.75 (s,2H), 1.96 (s, 3H), 1.49 (s, 9H).

Step 3. tert-butyl8,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxylate. A mixture oftert-butyl 8,10-dimethyl-11-oxo-1,3,4,9-tetrahydropyrido[2,3] pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (3.00 mg, 9.03 μmol, 0.11 eq),tert-butyl8,10-dimethyl-11-oxo-1,3,4,7-tetrahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(27.00 mg, 81.23 mol, 1.00 eq) in MeOH (5.00 mL) was Pd/C (10.00 mg,4.51 μmol, 0.10 eq) under N₂. The suspension was degassed under vacuumand purged with H₂ several times. The mixture was stirred under H₂ (50psi) at 25° C. for 16 hr. LCMS showed the starting material was consumedcompletely, the desired product was major. The reaction mixture wasdiluted with DCM/MeOH=1/1 (50 mL) and filtered. The filterate wasconcentrated to give the title compound (15.00 mg, 44.86 μmol, 99.40%yield) as a white solid, which was used directly for the next step. ¹HNMR (400 MHz, CDCl₃) δ 4.61 (br. s., 2H) 4.37 (dd, J=14.05, 6.78 Hz, 1H)3.95 (dd, J=13.99, 5.58 Hz, 1H) 3.60-3.81 (m, 2H) 3.33-3.46 (m, 1H) 3.17(s, 3H) 3.03-3.12 (m, 1H) 2.75 (br. s., 2H) 2.52-2.66 (m, 1H) 1.44-1.54(m, 9H) 1.10 (d, J=6.78 Hz, 3H). LCMS: 335 [M+1].

Step 4.8,10-dimethyl-3,4,7,8,9,10-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11(2H)-one.A mixture of tert-butyl 8,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (38.00 mg, 113.63 μmol,1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL,118.86 eq), and then the mixture was stirred at 10° C. for 1 hour. TLCshowed the starting material was consumed completely and a new spotappeared. The mixture was concentrated in vacuum to give the titlecompound as the TFA salt (39.58 mg, 113.63 μmol, 100.00% yield) as ayellow oil, which was used directly for the next step.

Step 5.N-(3-chloro-4-fluoro-phenyl)-8,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.A mixture of8,10-dimethyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(39.58 mg, 113.63 μmol, 1.00 eq, TFA), phenylN-(3-chloro-4-fluoro-phenyl)carbamate (45.28 mg, 170.45 μmol, 1.50 eq),TEA (23.00 mg, 227.26 μmol, 31.51 μL, 2.00 eq) in DCM (3.00 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 30° C. for 16 hour under N2 atmosphere. LCMS showed thestarting material was consumed completely and desired product was major.The mixture was poured into water (5 mL) and stirred at 5 min. Theaqueous phase was extracted with DCM (3 mL*3). The combined organicphase was washed with brine (5 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to give the title compound (15.00 mg, 36.59 μmol, 32.20%yield, 99% purity) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.61(m, 1H) 7.16-7.23 (m, 1H) 7.01-7.09 (m, 1H) 6.60 (s, 1H) 4.67 (s, 2H)4.37-4.48 (m, 1H) 3.99 (dd, J=14.06, 5.87 Hz, 1H) 3.79-3.92 (m, 2H)3.39-3.47 (m, 1H) 3.19 (s, 3H) 3.13 (s, 1H) 2.84 (s, 2H) 2.57-2.69 (m,1H) 1.13 (d, J=6.85 Hz, 3H). LCMS: 406 [M+1].

Compound 015:N-(3-chloro-4-fluoro-phenyl)-10-methyl-1l-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide

Step 1.10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.Tert-butyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 4, 40.00 mg, 124.85 μmol, 1.00 eq) was dissolved in TFA(2.46 g, 21.61 mmol, 1.60 mL, 173.09 eq) and stirred at 10° C. for 1 hr.TLC (DCM:MeOH=10:1) showed the starting material consumed. The mixturewas concentrated in vacuum. The residue was concentrated in vacuum toget10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-oneas the TFA salt (42.00 mg, crude) as colorless oil.

Step 2.N-(3-chloro-4-fluoro-phenyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide. To a solution of10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (42.00 mg, 125.64 μmol, 1.00 eq, TFA) in DCM (3.00 mL)was added phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (33.38 mg, 125.64mol, 1.00 eq) followed by TEA (63.57 mg, 628.20 mol, 87.08 μL, 5.00 eq).The mixture was stirred at 10° C. for 16 hr. LCMS showed one main peakwith desired Ms. The mixture was concentrated in vacuum. The residue waspurified by prep-HPLC (FA) to afford title compound (33.00 mg, 84.22μmol, 67.03% yield, 100% purity) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ=7.60 (dd, J=2.6, 6.7 Hz, 1H), 7.31 (ddd, J=2.6, 4.1, 9.0Hz, 1H), 7.11-7.19 (m, 1H), 4.70 (s, 2H), 4.37 (t, J=7.0 Hz, 2H), 3.83(t, J=5.8 Hz, 2H), 3.45-3.53 (m, 2H), 3.17 (s, 3H), 2.82 (t, J=5.8 Hz,2H), 2.28-2.38 (m, 2H).

Compound 016A:(S*)—N-(3-chloro-4-fluorophenyl)-8-methoxy-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide

* Pure but Unknown Stereochemistry E1.

Step 1. tert-butyl8-methoxy-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate. To a solution of tert-butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (Intermediate 3, 90.00mg, 267.55 mol, 1.00 eq) in THF (4.00 mL) was added NaH (16.05 mg,401.32 μmol, 60% purity, 1.50 eq) at 0° C., followed by Mel (75.95 mg,535.09 μmol, 33.31 μL, 2.00 eq) after 0.5 h. The mixture was stirred at15° C. for 1 h. The mixture was diluted with brine (30 mL), extractedwith EtOAc (30 mL, *2). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to give yellow oil, which waspurified by prep-TLC to the title compound (70.00 mg, 184.78 μmol,69.07% yield, 92.5% purity) as yellow solid. LCMS: 373[M+23].

Step 2. 8-methoxy-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo [2,4-b][1,4]diazepin-11-one. To a solution of tert-butyl8-methoxy-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (70.00 mg, 199.77 mol,1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL,135.22 eq) and the mixture was stirred at 15° C. under N₂ for 1 h. Themixture was concentrated in vacuo to afford the title compound as theTFA salt (72.00 mg, 177.87 μmol, 89.04% yield, 90% purity) as yellowoil, which was used directly for the next step. LCMS: 251[M+1].

Step 3.(S*)—N-(3-chloro-4-fluorophenyl)-8-methoxy-10-methyl-1-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide.A mixture of 8-methoxy-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (77.00 mg, 211.35 μmol, 1.00eq, TFA), Et₃N (106.93 mg, 1.06 mmol, 146.48 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (56.15 mg, 211.35 μmol, 1.00 eq)in DCM (4.00 mL) was stirred at 15° C. for 16 h. The mixture was dilutedwith DCM (30 mL*2) and washed with HCl (1 N, 30 mL). The organic phasewas dried over Na₂SO₄, filtered and concentrated in vacuo to give yellowoil. The oil was purified by prep-HPLC (FA) to get 48 mg of desiredproduct which was resolved via SFC (OD-3S_4_40_3 ML Column: ChiralcelOD-3 100×4.6 mm I.D., 3 um Mobile phase: 40% iso-propanol (0.05% DEA) inCO₂ Flow rate: 3 mL/min Wavelength: 220 nm) and further purified byprep-HPLC(FA) to get both enantiomers Compound 016_E1 (17.9 mg) andCompound 016_E2 (15.4 mg). LCMS: 422/424 [M+1]. ¹H NMR (400 MHz, CDCl₃)δ 7.59 (dd, J=2.63, 6.54 Hz, 1H), 7.16-7.23 (m, 1H), 7.03-7.10 (m, 1H),6.55 (s, 1H), 4.68 (d, J=5.26 Hz, 2H), 4.57 (dd, J=6.24, 14.43 Hz, 1H),4.29 (dd, J=5.93, 14.37 Hz, 1H), 4.08 (br t, J=5.01 Hz, 1H), 3.86 (q,J=5.75 Hz, 2H), 3.40-3.58 (m, 5H), 3.21 (s, 3H).

Compound 016B:(R*)—N-(3-chloro-4-fluorophenyl)-8-methoxy-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide

* Pure but Unknown Stereochemistry E2.

LCMS: 422/424 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (dd, J=2.63, 6.54Hz, 1H), 7.16-7.23 (m, 1H), 7.03-7.10 (m, 1H), 6.55 (s, 1H), 4.68 (d,J=5.26 Hz, 2H), 4.57 (dd, J=6.24, 14.43 Hz, 1H), 4.29 (dd, J=5.93, 14.37Hz, 1H), 4.08 (br t, J=5.01 Hz, 1H), 3.86 (q, J=5.75 Hz, 2H), 3.40-3.58(m, 5H), 3.21 (s, 3H).

Compound 017:N-(3-chloro-4-fluorophenyl)-8-ethoxy-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 016,using EtI instead of Mel in Step 1; to give yellow oil, which waspurified by prep-HPLC(FA) to afford the title compound (76.90 mg, 168.13μmol, 56.80% yield, 95.3% purity) as white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.59 (dd, J=2.64, 6.52 Hz, 1H), 7.20 (ddd, J=2.70, 4.08, 8.91Hz, 1H), 7.02-7.10 (m, 1H), 6.60 (s, 1H), 4.62-4.76 (m, 2H), 4.57 (dd,J=6.34, 14.24 Hz, 1H), 4.21-4.34 (m, 1H), 4.12-4.21 (m, 1H), 3.86 (t,J=6.27 Hz, 2H), 3.64 (ddt, J=2.13, 7.00, 13.76 Hz, 2H), 3.47 (dq,J=4.58, 15.04 Hz, 2H), 3.21 (s, 3H), 2.85 (q, J=5.48 Hz, 2H), 1.27 (t,J=6.96 Hz, 3H). LCMS: 436/438 [M+1].

Compound 018:N-(3-chloro-4-fluorophenyl)-8-(2,2-difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 016,using 2, 2-difluoroethyl trifluoromethanesulfonate instead of Mel inStep 1.

Step 1.tert-butyl-8-(2,2-difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (100.00 mg, 297.27μmol, 1.00 eq) in THF (3.00 mL) was added NaH (35.67 mg, 891.82 μmol,22.70 μL, 60% purity, 3.00 eq) with stirring at 0° C. for 0.5 h underN₂. Then 2, 2-difluoroethyl trifluoromethanesulfonate (2.97 mmol, 10.00eq) in DCM (7.4 mL) was added. The mixture was stirred at 15° C. for 2h. TLC showed that the starting material was consumed completely and onemain spot formed. The mixture was poured into 10 mL of ice water andextracted with EtOAc (10 mL*3). The organic layers was combined anddried over anhydrous Na₂SO₄, filtered and concentrated. The resultingresidue combined with another batch reaction mixture (50 mg of startingmaterial) was purified by prep-TLC (PE: EtOAc=1:5) to afford the titlecompound (140.00 mg, 349.63 μmol, 78.41% yield) as off-white oil.

Step 2.8-(2,2-difluoroethoxy)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl8-(2,2-difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(140.00 mg, 349.63 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54g, 13.51 mmol, 1.00 mL, 38.63 eq) with stirring at 15° C. for 1 h. TLC(PE: EtOAc=0:1) showed that the starting material was consumedcompletely and one major spot formed. The mixture was concentrated invacuo to give the the title compound as the TFA salt (200.00 mg, crude)as yellow oil and directly used in the next step.

Step 3.N-(3-chloro-4-fluorophenyl)-8-(2,2-difluoroethoxy)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of8-(2,2-difluoroethoxy)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (144.86 mg, 349.62 μmol, 1.00eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (102.17 mg,384.59 μmol, 1.10 eq) in DCM (2.00 mL) was added TEA (283.03 mg, 2.80mmol, 387.71 μL, 8.00 eq). The mixture was heated to 15° C. withstirring for 16 h. LCMS indicated that reactant8-(2,2-difluoroethoxy)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one was consumed completely and thedesired product was detected. The mixture was diluted with DCM (10 mL)and washed with HCl (1%, 10 mL*2) and brine (10 mL*1). The organic phasewas dried over anhydrous Na₂SO₄, filtered and concentrated. Theresulting residue was purified by prep-HPLC (FA) to give the titlecompound (93.60 mg, 189.64 μmol, 54.24% yield, 95.6% purity) as whitesolid. ¹H NMR (400 MHz, CDCl₃) δ=7.56 (br d, J=5.75 Hz, 1H), 7.14-7.21(m, 1H), 6.97-7.09 (m, 1H), 6.66 (br s, 1H), 5.73-6.06 (m, 1H),4.53-4.74 (m, 3H), 4.22-4.32 (m, 2H), 3.70-3.91 (m, 4H), 3.39-3.58 (m,2H), 3.19 (s, 3H), 2.75-2.89 (m, 2H). LCMS [M+1]: 472.

Compound 019:8-amino-N-(3-chloro-4-fluorophenyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.[2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-1-oxo-1.3.4,7,8,9-hexahydropyrido[2.3]pyrazolo[2,4-b][1,4]diazepin-8-yl]methanesulfonate.A mixture ofN-(3-chloro-4-fluoro-phenyl)-8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(Compound 004, 200.00 mg, 490.40 μmol, 1.00 eq) and TEA (297.74 mg, 2.94mmol, 407.87 μL, 6.00 eq) in DCM (5.00 mL) was added MsCl (224.70 mg,1.96 mmol, 151.83 μL, 4.00 eq) at 0° C. under N₂, and then the mixturewas stirred at 15° C. for 16 hours under N2 atmosphere. The mixture waspoured into water (5 mL) and stirred at 5 min. The aqueous phase wasextracted with DCM (3 mL*2). The combined organic phase was washed withbrine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum to afford the title compound (200.00 mg, 391.01 mol, 79.73%yield, 95% purity) as a white solid, which was used directly for thenext step. LCMS: 486/488 [M+1].

Step 2.8-azido-N-(3-chloro-4-fluoro-phenyl)-10-methyl-1-oxo-1,3,4,78,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide. To a solution of[2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]methanesulfonate(120.00 mg, 246.95 μmol, 1.00 eq) in DMF (2.00 mL) was added NaN₃ (32.11mg, 493.91 μmol, 17.36 μL, 2.00 eq) and the resulting mixture was heatedto 65° C. for 32 h. The mixture was diluted with EtOAc (20 mL) andwashed with brine (20 mL*3). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to afford the title compound (106.00mg, crude), which was used directly for the next step. LCMS: 433/435[M+1].

Step 3.8-amino-N-(3-chloro-4-fluorophenyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.A mixture of8-azido-N-(3-chloro-4-fluoro-phenyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(120.00 mg, 277.24 μmol, 1.00 eq), N14Cl (37.07 mg, 693.10 μmol, 24.23μL, 2.50 eq) and Zn (27.19 mg, 415.86 μmol, 1.50 eq) in H₂O (500.00uL)/EtOH (5.00 mL) was stirred at 30° C. for 16 hours. The mixture wasfiltered and the filtrate was concentrated in vacuo. The residue waspurified by prep-HPLC(FA) to afford (59.40 mg, 144.54 μmol, 52.14%yield, 99% purity) as yellow solid. LCMS: 407/409 [M+1]. ¹H NMR (400MHz, CDCl₃) δ 8.04 (s, 1H), 7.61 (dd, J=2.64, 6.53 Hz, 1H), 7.18-7.24(m, 1H), 7.04-7.11 (m, 1H), 6.62 (s, 1H), 4.69 (d, J=3.26 Hz, 2H), 4.54(dd, J=6.02, 14.30 Hz, 1H), 4.12 (dd, J=4.83, 14.24 Hz, 1H), 3.77-3.92(m, 3H), 3.54 (dd, J=5.14, 14.81 Hz, 1H), 3.11-3.27 (m, 4H), 2.86 (t,J=5.83 Hz, 2H).

Compound 020:N-(3-chloro-4-fluorophenyl)-8-(dimethylamino)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-(dimethylamino)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo [2,4-b][1,4]diazepine-2-carboxylate. To solution ofN-methylmethanamine (87.79 mg, 1.08 mmol, 98.64 μL, 3.00 eq, HCl) in THE(3.00 mL) was added AcONa (88.32 mg, 1.08 mmol, 3.00 eq), tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 2, 120.00 mg, 358.88 μmol, 1.00 eq), tetraethoxytitanium(245.59 mg, 1.08 mmol, 223.26 μL, 3.00 eq) and CH₃COOH (adjusted pH to6), and the mixture was stirred at 75° C. for 16 h. NaBH₃CN (22.55 mg,358.88 μmol, 1.00 eq) was added at 15° C. and the mixture was stirredfor another 2 h. The mixture was diluted with EtOAc (40 mL) and brine(20 mL) and filtered. The filtrate was washed with brine (40 mL). Theorganic phase was dried over Na₂SO₄, filtrated and concentrated invacuo, which was purified by prep-TLC twice to afford the title compound(43.00 mg, 100.56 mol, 28.02% yield, 85% purity) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 4.50-4.60 (m, 2H), 4.46-4.48 (m, 1H), 4.25-4.30 (m,1H), 3.78-3.82 (m, 1H), 3.52-3.56 (m, 2H), 3.17-3.35 (m, 5H), 2.70-2.80(m, 2H), 2.35 (s, 6H), 1.49 (s, 9H). LCMS: 364[M+1].

Step 2.8-(dimethylamino)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution oftert-butyl8-(dimethylamino)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(43.00 mg, 100.56 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g,13.51 mmol, 1.00 mL, 134.31 eq) and the mixture was stirred at 15° C.under N₂ for 1 h. TLC showed the reactant was consumed completely andone major new spot with larger polarity was detected. The mixture wasconcentrated in vacuo to afford the title compound (38.00 mg, crude,TFA) as yellow oil, which was used directly for the next step. LCMS: 264[M+1].

Step 3.N-(3-chloro-4-fluorophenyl)-8-(dimethylamino)-10-methyl-1l-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.A mixture of 8-(dimethylamino)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (38.00 mg, 100.70 μmol, 1.00eq, TFA), Et₃N (50.95 mg, 503.50 μmol, 69.79 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (26.75 mg, 100.70 μmol, 1.00 eq)in DCM (4.00 mL) was stirred at 15° C. for 16 h. The mixture was dilutedwith DCM (30 mL) and washed with HCl (1M, 30 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo to give yellowoil. The oil was purified by prep-HPLC (FA) to afford the title compound(33.00 mg, 75.12 μmol, 74.60% yield, 99% purity) as white solid. ¹H NMR(400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.60 (dd, J=2.69, 6.48 Hz, 1H),7.19-7.25 (m, 1H), 7.02-7.11 (m, 1H), 6.71 (s, 1H), 4.53-4.80 (m, 3H),4.35 (dd, J=6.30, 14.86 Hz, 1H), 3.80-3.93 (m, 2H), 3.54-3.65 (m, 1H),3.38-3.50 (m, 2H), 3.20 (s, 3H), 2.85 (t, J=5.75 Hz, 2H), 2.42 (s, 6H).LCMS: 435/437[M+1].

Compound 021:N-(3-chloro-4-fluorophenyl)-10-methyl-8-morpholino-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl10-methyl-8-morpholino-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (Intermediate 2, 150.00 mg,448.60 μmol, 1.00 eq), morpholine (78.16 mg, 897.20 μmol, 78.95 μL, 2.00eq), CH₃COOH (26.94 mg, 448.60 μmol, 25.66 μL, 1.00 eq) and 4A molecularsieve (250.00 mg) in DCE (4.00 mL) was stirred at 20° C. for 3 h.NaBH₃CN (140.95 mg, 2.24 mmol, 5.00 eq) was added and the mixture wasstirred at 20° C. for 16 h. The mixture was diluted with EtOAc (40 mL)and washed with brine (30 mL). The organic phase was dried over Na₂SO₄,filtrated and concentrated in vacuo to give oil, which was purified byprep-TLC to afford the title compound (72.00 mg, 174.01 μmol, 38.79%yield, 98% purity) as yellow oil. LCMS: 406[M+1].

Step 2.10-methyl-8-morpholino-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl10-methyl-8-morpholino-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(78.00 mg, 192.36 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g,27.01 mmol, 2.00 mL, 140.43 eq) and the mixture was stirred at 15° C.under N₂ for 1 h. The mixture was concentrated in vacuo to afford thetitle compound as the TFA salt (80.00 mg, 190.75 μmol, 99.16% yield) asyellow oil, which was used directly for the next step.

Step 3.N-(3-chloro-4-fluorophenyl)-10-methyl-8-morpholino-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of10-methyl-8-morpholino-2,3,4,7,8,9-hexahydro-1H-pyrido [2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (80.00 mg, 190.75 μmol, 1.00 eq, TFA), Et₃N(96.51 mg, 953.75 μmol, 132.21 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (55.74 mg, 209.83 μmol, 1.10 eq)in DCM (5.00 mL) was stirred at 25° C. for 16 h. The mixture was dilutedwith DCM (30 mL) and washed with HCl (1 M, 30 mL*2). The organic phasewas dried over Na₂SO₄, filtered and concentrated in vacuo. The resultingresidue was purified by prep-HPLC(FA) to afford the title compound(53.00 mg, 116.02 μmol, 57.68% yield, 99% purity) as white solid. ¹H NMR(400 MHz, CDCl₃) δ 7.60 (dd, J=2.63, 6.54 Hz, 1H), 7.18-7.25 (m, 1H),7.03-7.11 (m, 1H), 6.62 (s, 1H), 4.69 (d, J=12.23 Hz, 2H), 4.58 (dd,J=3.91, 14.67 Hz, 1H), 4.36 (dd, J=6.36, 14.67 Hz, 1H), 3.78-3.96 (m,2H), 3.73 (br t, J=4.10 Hz, 4H), 3.55-3.65 (m, 1H), 3.39 (br d, J=10.88Hz, 2H), 3.20 (s, 3H), 2.86 (t, J=5.75 Hz, 2H), 2.66-2.76 (m, 2H),2.52-2.63 (m, 2H). LCMS: 477/479[M+1].

Compound 022:N-(3-chloro-4-fluorophenyl)-8-(3,3-difluoroazetidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-(3,3-difluoroazetidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of 3,3-difluoroazetidine; hydrochloride (116.22 mg, 897.20μmol, 2.00 eq) and NaOAc (73.60 mg, 897.20 μmol, 2.00 eq) in DCE (4.00mL) was stirred at 25° C. for 0.5 h, tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (Intermediate 2, 150.00 mg,448.60 μmol, 1.00 eq) and 4A molecular sieve (250.00 mg) was added andthe mixture was stirred for 3 h. NaBH₃CN (140.95 mg, 2.24 mmol, 5.00 eq)was added and the mixture was stirred at 25° C. for 16 h. The mixturewas diluted with EtOAc (40 mL) and washed with brine (30 mL). Theorganic phase was dried over Na₂SO₄, filtrated and concentrated in vacuoto give oil, which was purified by prep-TLC to afford the title compound(120.00 mg, 288.73 mol, 64.36% yield, 99% purity) as yellow oil. LCMS:412[M+1].

Step 2.8-(3,3-difluoroazetidin-1-yl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl8-(3,3-difluoroazetidin-1-yl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(80.00 mg, 194.43 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g,27.01 mmol, 2.00 mL, 138.93 eq) and the mixture was stirred at 15° C.under N₂ for 1 h. The mixture was concentrated in vacuo to afford thetitle compound (82.00 mg, 192.78 μmol, 99.15% yield, TFA) as yellow oil,which was used directly for the next step.

Step 3.N-(3-chloro-4-fluorophenyl)-8-(3,3-difluoroazetidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of8-(3,3-difluoroazetidin-1-yl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(82.00 mg, 192.78 μmol, 1.00 eq, TFA), Et₃N (97.54 mg, 963.91 μmol,133.61 μL, 5.00 eq) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate(56.34 mg, 212.06 mol, 1.10 eq) in DCM (5.00 mL) was stirred at 22° C.for 16 h. The mixture was diluted with DCM (30 mL) and washed with HCl(1 M, 30 mL*2). The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was purified byprep-HPLC(FA) to afford the title compound (50.00 mg, 102.51 μmol,53.17% yield, 99% purity) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.59(dd, J=2.64, 6.53 Hz, 1H), 7.16-7.24 (m, 1H), 7.02-7.11 (m, 1H), 6.56(s, 1H), 4.68 (d, J=1.76 Hz, 2H), 4.40 (dd, J=6.09, 14.12 Hz, 1H), 4.13(dd, J=5.96, 14.12 Hz, 1H), 3.82-3.93 (m, 2H), 3.74 (br d, J=4.89 Hz,4H), 3.36-3.47 (m, 1H), 3.20 (s, 5H), 2.86 (br d, J=5.02 Hz, 2H), 2.03(s, 1H). LCMS: 483/485 [M+1].

Compound 023:8-(azetidin-1-yl)-N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-(azetidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of azetidine (51.23 mg, 897.20 μmol, 60.27 μL, 2.00 eq) andNaOAc (73.60 mg, 897.20 μmol, 2.00 eq) in DCE (4.00 mL) was stirred at25° C. for 0.5 h, tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 2, 150.00 mg, 448.60 μmol, 1.00 eq) and 4A molecular sieve(250.00 mg) was added and the mixture was stirred for 3 h. NaBH₃CN(140.95 mg, 2.24 mmol, 5.00 eq) was added and the mixture was stirred at25° C. for 16 h. The mixture was diluted with EtOAc (40 mL) and brine(30 mL). The organic phase was dried over Na₂SO₄, filtrated andconcentrated in vacuo. The resulting oil was purified by prep-TLC toafford the title compound (85.00 mg, 181.11 μmol, 40.37% yield, 80%purity) as yellow oil. LCMS: 398[M+23].

Step 2.8-(azetidin-1-yl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl8-(azetidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(106.25 mg, 226.38 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08g, 27.01 mmol, 2.00 mL, 119.33 eq) and the mixture was stirred at 15° C.under N₂ for 1 h. The mixture was concentrated in vacuo to afford thetitle compound (88.00 mg, 226.01 mol, 99.83% yield, TFA) as yellow oil,which was used directly for the next step.

Step 3.8-(azetidin-1-yl)-N-(3-chloro-4-fluorophenyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of8-(azetidin-1-yl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (88.00 mg, 226.01 μmol, 1.00 eq,TFA), Et₃N (114.35 mg, 1.13 mmol, 156.64 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl) carbamate (66.05 mg, 248.61 μmol, 1.10 eq)in DCM (5.00 mL) was stirred at 15° C. for 16 h. The mixture was dilutedwith DCM (30 mL) and washed with HCl (1 M, 30 mL*2). The organic phasewas dried over Na₂SO₄, filtered and concentrated in vacuo to giveresidue, which was purified by prep-HPLC(FA) to afford the titlecompound (52.80 mg, 118.15 μmol, 52.28% yield) as yellow solid. ¹H NMR(400 MHz, CDCl₃) δ=8.06 (s, 1H), 7.60 (dd, J=2.69, 6.60 Hz, 1H),7.17-7.25 (m, 1H), 7.03-7.11 (m, 1H), 6.64 (s, 1H), 4.68 (s, 2H),4.34-4.45 (m, 1H), 4.20-4.33 (m, 1H), 3.76-3.96 (m, 2H), 3.53 (br s,5H), 3.29 (br s, 2H), 3.19 (s, 3H), 2.80-2.89 (m, 2H), 2.26-2.30 (m,2H). LCMS: 447/449[M+1].

Compound 024:N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-8-(pyrrolidin-1-yl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl10-methyl-11-oxo-8-pyrrolidin-1-yl-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (Intermediate 2, 150.00 mg,448.60 μmol, 1.00 eq), pyrrolidine (63.81 mg, 897.20 μmol, 75.07 μL,2.00 eq), CH₃COOH (26.94 mg, 448.60 μmol, 25.66 μL, 1.00 eq) and 4Amolecular sieve (250.00 mg, 448.60 μmol, 1.00 eq) in DCE (4.00 mL) wasstirred at 20° C. for 3 h. NaBH₃CN (140.95 mg, 2.24 mmol, 5.00 eq) wasadded and the mixture was stirred at 20° C. for 16 h. The mixture wasdiluted with EtOAc (40 mL) and washed with brine (60 mL). The organicphase was dried over Na₂SO₄, filtrated and concentrated in vacuo to giveoil, which was purified by prep-TLC to afford the title compound (138.00mg, 350.77 μmol, 78.19% yield, 99% purity) as yellow oil. LCMS:390[M+1].

Step 2.10-methyl-8-pyrrolidin-1-yl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl10-methyl-11-oxo-8-pyrrolidin-1-yl-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(80.00 mg, 205.40 μmol, 1.00 eq) in DCM (4.50 mL) was added TFA (6.93 g,60.78 mmol, 4.50 mL, 295.90 eq) and the mixture was stirred at 20° C.under N₂ for 1 h. The mixture was concentrated in vacuo to afford thetitle compound (82.86 mg, 205.40 μmol, 100.00% yield, TFA) as yellowoil, which was used directly for the next step.

Step 3.N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-8-(pyrrolidin-1-yl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.A mixture of 10-methyl-8-pyrrolidin-1-yl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3] pyrazolo[2,4-b][1,4]diazepin-11-one (82.86 mg, 205.40 μmol, 1.00eq, TFA), Et₃N (103.92 mg, 1.03 mmol, 142.36 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl) carbamate (60.03 mg, 225.94 mol, 1.10 eq)in DCM (5.00 mL) was stirred at 22° C. for 16 h. The mixture was dilutedwith DCM (30 mL) and washed with HCl (1 M, 30 mL*2). The organic phasewas dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by prep-HPLC(FA) to afford the title compound (21.65 mg,46.50 μmol, 22.64% yield, 99% purity) as white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.56-7.58 (m, 1H), 7.18-7.19 (m, 1H), 7.02-7.06 (m, 1H), 6.71(s, 1H), 4.66-4.72 (m, 2H),4.49-4.55 (m, 2H), 3.83-3.88 (m, 2H),3.63-3.65 (m, 3H), 3.18 (s, 3H), 2.96-3.04 (m, 4H), 2.82-2.85 (m, 2H),1.95-2.00 (m, 4H). LCMS: 461/463 [M+1].

Compound 025:N-(3-chloro-4-fluorophenyl)-10-methyl-8-(methylthio)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.[2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]methanesulfonate. A mixture ofN-(3-chloro-4-fluoro-phenyl)-8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(Compound 004, 100.00 mg, 245.20 μmol, 1.00 eq), TEA (49.62 mg, 490.40μmol, 67.97 μL, 2.00 eq) in DCM (5.00 mL) was added MsCl (42.13 mg,367.80 μmol, 28.47 μL, 1.50 eq) at 0° C. under N₂, and then the mixturewas stirred at 15° C. for 16 hr under N₂ atmosphere. TLC showed thestarting material/desired product=1/3. Then MsCl (14 mg, 122.6 μmol,9.49 μL, 0.50 eq) was added to the mixture, the mixture was stirred at15° C. for 4 hr, TLC showed the starting material/desired product=1/3.The mixture was stirred at 50° C. for 2 hr, TLC showed the startingmaterial/desired product=1/3. The mixture was poured into water (5 mL)and stirred at 5 min. The aqueous phase was extracted with ethyl acetate(3 mL*2). The combined organic phase was washed with brine (5 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by prep-TLC to afford the title compound (82.00 mg, 162.00μmol, 66.07% yield, 96% purity) as a white solid. LCMS: 486 [M+1]

Step 2:N-(3-chloro-4-fluorophenyl)-10-methyl-8-(methylthio)-11-oxo-1,3,4,7,8,9,1011-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.A mixture of[2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]methanesulfonate(50.00 mg, 102.90 μmol, 1.00 eq) in DMF (2.00 mL) was added sodium;methanethiolate (50.48 mg, 720.30 μmol, 45.89 μL, 7.00 eq) at 0° C.under N₂, and then the mixture was stirred at 15° C. for 2 hour under N₂atmosphere. LCMS showed the starting material was consumed completely,desired product/byproduct=1/1. The mixture was poured into ice-water (10mL) and stirred at 5 min. The aqueous phase was extracted with ethylacetate (5 mL*3). The combined organic phase was washed with brine (10mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by Prep-HPLC (FA) to afford the title compound(18.00 mg, 40.28 μmol, 39.15% yield, 98% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.58 (dd, J=2.6, 6.5 Hz, 1H), 7.18 (s, 1H),7.02-7.09 (m, 1H), 6.55 (s, 1H), 4.64-4.74 (m, 3H), 4.22-4.33 (m, 1H),3.81-3.90 (m, 2H), 3.69 (dd, J=4.5, 14.8 Hz, 1H), 3.36-3.54 (m, 2H),3.23 (s, 3H), 2.85 (br d, J=4.6 Hz, 2H), 2.24 (s, 3H). LCMS: 438/440[M+1]; andN-(3-chloro-4-fluorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamideas a by-product.

Compound 026A:N-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylsulfinyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide:Pure but Unknown Diastereomer D1

Step 1.tert-butyl-10-methyl-8-methylsulfonyloxy-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate. To a solution of tert-butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (220.00 mg, 654.00μmol, 1.00 eq) in DCM (2.00 mL) was added methanesulfonyl chloride(89.90 mg, 784.80 μmol, 60.74 μL, 1.20 eq). The mixture was stirred at10° C. for 4 hr. TLC (Dichloromethane: Methanol=10:1) showed the mixturewas completed. The mixture was quenched with water (20 mL), extractedwith ethyl acetate (10 mL*3), the organic layer was washed with brine(10 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo to affordthe title compound (200.00 mg, 482.53 μmol, 73.78% yield) as colorlessoil.

Step 2.tert-butyl-8-acetylsulfanyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl10-methyl-8-methylsulfonyloxy-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(220.00 mg, 530.79 μmol, 1.00 eq) in DMF (2.00 mL) was addedacetylsulfanylpotassium (181.86 mg, 1.59 mmol, 3.00 eq). The mixture wasstirred at 80° C. for 16 hr. LCMS showed the reaction was complete. Themixture was quenched by addition water (10 mL), and extracted with ethylacetate (10 mL*3). The organic layer was washed with water (10 mL) andbrine (10 mL) and dried over anhydrous Na₂SO₄, concentrated in vacuum togive the residue which was purified by prep-TLC(Dichloromethane:Methanol=10:1) to afford the title compound (170.00 mg,396.46 μmol, 74.69% yield, 92% purity) as yellow oil.

Step 3. tert-butyl10-methyl-8-methylsulfanyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl8-acetylsulfanyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(150.00 mg, 380.24 μmol, 1.00 eq) in MeOH (2.00 mL) was added K₂CO₃(157.66 mg, 1.14 mmol, 3.00 eq). The mixture was stirred at 15° C. for15 mins, while Mel (59.37 mg, 418.26 μmol, 26.04 μL, 1.10 eq) was added,the mixture was stirred at 15° C. for 15 mins. LCMS showed the reactioncomplete. The mixture was concentrated in vacuum to give the residuewhich was washed with DCM (30 mL) and filtered, the filtrate wasconcentrated in vacuum to afford the title compound (132.00 mg, 356.58mol, 93.78% yield, 99% purity) as colorless oil.

Step 4. 10-methyl-8-methylsulfanyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo [2,4-b][1,4]diazepin-11-one. To a solution of tert-butyl10-methyl-8-methylsulfanyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(150.00 mg, 409.30 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08g, 27.01 mmol, 2.00 mL, 66.00 eq), the mixture was stirred at 15° C. for30 min. TLC (Dichloromethane: Methanol=10:1) showed the reaction wascompleted. The mixture was concentrated to afford the title compound(140.00 mg, 368.05 mol, 89.92% yield, TFA) as white solid.

Step 5.N-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylsulfanyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a solution of10-methyl-8-methylsulfanyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (140.00 mg, 368.05 mol, 1.00 eq,TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (97.78 mg, 368.05μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (93.11 mg, 920.13 μmol,127.55 μL, 2.50 eq). The mixture was stirred at 15° C. for 16 hr. LCMSshowed the reaction was completed. The mixture was quenched by water (10mL) and extracted with ethyl acetate (30 mL). The organic layer waswashed with brine (10 mL), dried over anhydrou Na₂SO₄ and concentratedin vacuum to afford the title compound (200.00 mg, 365.36 μmol, 99.27%yield, 80% purity) as white solid.

Step 6.N-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylsulfinyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamideTo a solution ofN-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylsulfanyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(100.00 mg, 228.35 μmol, 1.00 eq) and (Bu₃Sn)₂O (204.18 mg, 342.53 mol,174.52 μL, 1.50 eq) in DCM (3.00 mL) was added Br₂ (54.74 mg, 342.53μmol, 17.66 μL, 1.50 eq) in DCM (500.00 uL) for 30 min. The mixture wasstirred at 15° C. for 2 hr. LCMS showed the reactant remained, thenanother batch of (Bu₃Sn)₂O (272.24 mg, 456.70 mol, 232.69 μL, 2.00 eq)and Br₂ (72.99 mg, 456.70 μmol, 23.54 μL, 2.00 eq) was added in turn.The mixture was stirred for another 2 hr. LCMS showed the reaction wascompleted. The mixture was washed with saturated KF (10 mL), the organiclayer was concentrated in vacuum. The residue was purified by prep-HPLCto giveN-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylsulfinyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(50.00 mg, 106.85 μmol, 46.79% yield, 97% purity) as yellow oil, 35 mgof which was separated by SFC (column: AS (250 mm*30 mm, 10 um); mobilephase: [Neu-ETOH]; Gradient Time (min): 5.5 minute, 80 minutes),followed by prep-HPLC to afford two isomers Compound 026, D1 (peak1, 14mg), and Compound 026, D2 (peak 2, 18 mg). Compound 026, D1: ¹H NMR (400MHz, CDCl₃) δ 7.58 (dd, J=2.51, 6.42 Hz, 1H), 7.15-7.24 (m, 1H),7.01-7.11 (m, 1H), 6.64 (s, 1H), 4.18-4.83 (m, 4H), 3.64-4.05 (m, 4H),3.44-3.58 (m, 1H), 3.23 (d, J=13.94 Hz, 3H), 2.84 (br d, J=4.77 Hz, 2H),2.63-2.74 (m, 3H).

Compound 026B:N-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylsulfinyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide:Pure but Unknown Diastereomer D2

Compound 026, D2: ¹H NMR (400 MHz, CDCl₃) δ 7.57 (dd, J=2.63, 6.54 Hz,1H), 7.17-7.24 (m, 1H), 7.01-7.10 (m, 1H), 6.70 (s, 1H), 4.18-4.87 (m,4H), 3.64-4.02 (m, 4H), 3.42-3.60 (m, 1H), 3.23 (d, J=13.82 Hz, 3H),2.77-2.91 (m, 2H), 2.62-2.74 (m, 3H).

Compound 027:N-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylsulfonyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide

To a solution ofN-(3-chloro-4-fluoro-phenyl)-10-methyl-8-methylsulfanyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(Compound 26, product from Step 5, 50.00 mg, 114.18 μmol, 1.00 eq) inDCM (2.00 mL) was added n-CPBA (123.15 mg, 570.88 μmol, 80% purity, 5.00eq). The resulting solution was stirred at 15° C. for 2 hr. LCMS showedthe reaction was complete. The mixture was quenched with water (10 mL),the organic layer was washed with sat. NaHCO₃ (10 mL) and brine (10 mL),dried over anhydrous Na₂SO₄ and concentrated in vacuum. The mixture waspurified by prep-HPLC to afford the title compound (17.00 mg, 35.81μmol, 31.37% yield, 99% purity) as the white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.57 (dd, J=2.70, 6.46 Hz, 1H), 7.16-7.23 (m, 1H), 7.02-7.10(m, 1H), 6.66 (s, 1H), 4.83-4.93 (m, 1H), 4.58-4.79 (m, 3H), 3.74-3.98(m, 5H), 3.22 (s, 3H), 2.95 (s, 3H), 2.84 (t, J=5.83 Hz, 2H). LCMS:470/472 [M+1].

Compound 028: Methyl2-(2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-8-yl)acetate

Step 1. tert-butyl(8E)-8-(2-methoxy-2-oxo-ethylidene)-10-methyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2.3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of methyl 2-dimethoxyphosphorylacetate (162.85 mg, 894.22μmol, 129.25 μL, 1.30 eq) in THE (10.00 mL) was added potassium2-methylpropan-2-olate (115.78 mg, 1.03 mmol, 1.50 eq) at 0° C. for 10min. Then the mixture was added tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (230.00 mg, 687.86 μmol, 1.00 eq)and the mixture was stirred at 15° C. for 4 h. The reaction mixture wasquenched with H₂O (10 mL), diluted with brine (40 mL) and extracted withEtOAc (30 mL*2). The combined organic phase was washed with brine (30mL*2), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography to affordthe title compound (164.00 mg, 382.25 μmol, 55.57% yield, 91% purity) asa yellow oil. LCMS: 391 [M+1].

Step 2. tert-butyl8-(2-methoxy-2-oxo-ethyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl(8E)-8-(2-methoxy-2-oxo-ethylidene)-10-methyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(200 mg, 512.26 mol, 1.00 eq) in MeOH (10.00 mL) was added Pd/C (50.00mg, 10% purity) and the mixture was stirred at 15° C. under H₂ (15 psi)for 16 h. The reaction mixture was filtered and the filterate wasconcentrated in vacuo to afford the title compound (195.00 mg, 472.03mol, 92.15% yield, 95% purity) as a oil, which was used directly for thenext step. LCMS: 393 [M+1].

Step 3. methyl2-(10-methyl-11-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl)acetate.To a solution of tert-butyl8-(2-methoxy-2-oxo-ethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(195.00 mg, 496.88 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (4.62g, 40.52 mmol, 3.00 mL, 81.55 eq) and the mixture was stirred at 15° C.for 1 h. The mixture was concentrated in vacuo to afford the titlecompound (190.00 mg, 448.86 mol, 90.34% yield, 96% purity, TFA), whichwas used directly for the next step.

Step 4. methyl2-(2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-8-yl)acetate.A mixture of methyl 2-(10-methyl-11-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3] pyrazolo[2,4-b][1,4]diazepin-8-yl)acetate (195.00 mg, 479.87 μmol,1.00 eq, TFA), Et₃N (242.79 mg, 2.40 mmol, 332.59 μL, 5.00 eq) andphenyl N-(3-chloro-4-fluoro-phenyl)carbamate (127.49 mg, 479.87 μmol,1.00 eq) in DCM (5.00 mL) was stirred at 15° C. for 16 h. The mixturewas diluted with DCM (30 mL) and washed with HCl (1 M, 30 mL*2). Theorganic phase was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography to afford desiredproduct (180 mg, 97% purity), 40 mg of which was further purified byprep-HPLC(FA) to afford the title compound (35.7 mg, 99% purity) aswhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.59 (m, 1H), 7.16-7.27 (m,1H), 7.03-7.07 (t, J=8.8 Hz, 1H), 6.56 (s, 1H), 4.66-4.67 (m, 2H),4.45-4.47 (m, 1H), 4.12-4.15 (m, 1H), 3.84-3.86 (m, 2H), 3.74 (s, 3H),3.46-3.48 (m, 1H), 3.18-3.26 (m, 4H), 2.95-3.05 (m, 1H), 2.82-2.85 (m,2H), 2.39-2.51 (m, 2H). LCMS: 464/466 [M+1].

Compound 029:N-(3-chloro-4-fluorophenyl)-8-(2-hydroxyethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

To a solution of methyl2-[2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]acetate(Compound 028, 40.00 mg, 86.23 μmol, 1.00 eq) in THF (3.00 mL) was addedLiBH₄ (5.63 mg, 258.69 μmol, 3.00 eq) at 0° C. and the mixture wasstirred at 15° C. for 4 h. The reaction mixture was quenched with H₂O(20 mL) at 0° C. and extracted with ethyl acetate (20 mL*2). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue, which was purified byprep-HPLC(FA) to afford the title compound (18.50 mg, 42.02 μmol, 48.73%yield, 99% purity) as a white solid. ¹H NMR (400 MHz, CD₃CN) δ 7.64-7.66(m, 1H), 7.44 (s, 1H), 7.31-7.32 (m, 1H), 7.11-7.15 (t, J=9.0 Hz, 1H),4.59 (s, 2H), 4.34-4.36 (m, 1H), 4.06-4.10 (m, 1H), 3.73-3.75 (m, 2H),3.59-3.62 (m, 2H), 3.36-3.39 (m, 1H), 3.08-3.13 (m, 4H), 2.73-2.76 (m,2H), 2.55-2.65 (m, 1H), 1.52-1.55 (m, 2H). LCMS: 436/438 [M+1].

Compound 030: Ethyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate

Step 1. ethyl 2-[[tert-butoxycarbonyl(methyl)amino]methyl]prop-2-enoate.A mixture of tert-butyl N-methylcarbamate (200.00 mg, 1.52 mmol, 1.00eq) in THE (5.00 mL) was added NaH (91.20 mg, 2.28 mmol, 60% purity,1.50 eq) at 0° C. for 0.5 hr under N₂, then ethyl2-(bromomethyl)prop-2-enoate (352.10 mg, 1.82 mmol, 1.20 eq) was addedto the mixture dropwise at 0° C., and the mixture was stirred at 15° C.for 2 hr under N2 atmosphere. TLC showed the starting material wasconsumed completely, two new spots appeared. The mixture was poured intoice-water (10 mL) and stirred at 5 min. The aqueous phase was extractedwith ethyl acetate (5 mL*3). The combined organic phase was washed withbrine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=100/1 to 5/1) to afford the title compound(112.00 mg, 460.34 μmol, 30.29% yield) as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ 6.28 (s, 1H), 5.55 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 4.07(br s, 2H), 2.88 (br s, 3H), 1.45 (br s, 9H), 1.31 (br s, 3H).

Step 2. ethyl2-(methylaminomethyl)prop-2-enoate. A mixture of ethyl2-[[tert-butoxycarbonyl(methyl)amino]methyl]prop-2-enoate (112.00 mg,460.34 mol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (4 M,5.00 mL, 43.45 eq), and then the mixture was stirred at 15° C. for 0.5hour. TLC showed the starting material was consumed completely, a newspot was major. The mixture was concentrated in vacuum to afford thetitle compound (82.50 mg, 459.25 μmol, 99.76% yield, HCl) as a whitesolid, which was used directly for next step.

Step 3. tert-butyl 3-[2-ethoxycarbonylallyl (methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate. Amixture of5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylicacid (80.00 mg, 299.31 μmol, 1.00 eq), ethyl 2-(methylaminomethyl)prop-2-enoate (59.14 mg, 329.24 μmol, 1.10 eq, HCl), T₃P (285.70 mg,897.93 μmol, 267.01 μL, 3.00 eq), TEA (151.44 mg, 1.50 mmol, 207.45 μL,5.00 eq) in THE (3.00 mL) was degassed and purged with N₂ for 3 times,and then the mixture was stirred at 15° C. for 16 hour under N₂atmosphere. TLC showed the starting material was consumed completely anda new spot appeared. The mixture was poured into water (10 mL) andstirred at 5 min. The aqueous phase was extracted with ethyl acetate (5mL*3). The combined organic phase was washed with brine (10 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by Prep-TLC (DCM/MeOH=10/1) to afford the title compound(46.00 mg, 105.49 μmol, 35.24% yield, 90% purity) as a white solid.LCMS: 393 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 6.35 (s, 1H), 5.67 (br s,1H), 4.63 (s, 4H), 4.18-4.30 (m, 2H), 3.71 (br s, 2H), 2.91-3.47 (m,3H), 2.74 (br t, J=5.4 Hz, 2H), 1.48 (s, 9H), 1.31 (t, J=7.2 Hz, 3H).

Step 4. 2-tert-butyl 8-ethyl10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,8(7H)-dicarboxylate.A mixture of tert-butyl3-[2-ethoxycarbonylallyl(methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(36.00 mg, 91.73 μmol, 1.00 eq), DBU (6.98 mg, 45.87 μmol, 6.91 μL, 0.50eq) in MeCN (1.00 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 50° C. for 2 hour under N2 atmosphere.TLC showed the starting material was consumed completely and desiredproduct was major. The mixture was poured into water (5 mL) and stirredat 5 min. The aqueous phase was extracted with ethyl acetate (3 mL*3).The combined organic phase was washed with brine (5 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by Prep-TLC (DCM/MeOH=20/1) to give the title compound (20.00mg, 50.96 μmol, 55.56% yield) as a white solid. LCMS: 393 [M+1]Step 5.ethyl 10-methyl-1-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate. A mixture of2-tert-butyl 8-ethyl10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,8(7H)-dicarboxylate(22.00 mg, 56.06 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g,13.51 mmol, 1.00 mL, 240.93 eq), and then the mixture was stirred at 15°C. for 1 hour. TLC showed the starting material was consumed completely,a new spot appeared. The mixture was concentrated in vacuum to affordthe title compound (22.70 mg, 55.86 μmol, ⁹⁹0.65% yield, TFA) as ayellow oil, which was used directly for next step.

Step 6. ethyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-1-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate.A mixture of ethyl10-methyl-11-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate(22.00 mg, 54.14 μmol, 1.00 eq, TFA), phenylN-(3-chloro-4-fluoro-phenyl)carbamate (15.82 mg, 59.55 μmol, 1.10 eq)and TEA (10.96 mg, 108.28 μmol, 15.01 μL, 2.00 eq) in DCM (3.00 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 15° C. for 16 hour under N2 atmosphere. LCMS showed thestarting material was consumed completely, desired product was major.The mixture was poured into water (5 mL) and stirred at 5 min. Theaqueous phase was extracted with DCM (3 mL*3). The combined organicphase was washed with brine (5 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byPrep-HPLC (FA) to afford the title compound (15.00 mg, 32.01 μmol,59.13% yield, 99% purity) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ7.58 (dd, J=2.6, 6.5 Hz, 1H), 7.16-7.22 (m, 1H), 7.02-7.09 (m, 1H), 6.58(s, 1H), 4.50-4.76 (m, 4H), 4.27 (d, J=7.1 Hz, 2H), 3.73-3.91 (m, 3H),3.58-3.70 (m, 1H), 3.33-3.43 (m, 1H), 3.19 (s, 3H), 2.84 (br d, J=5.4Hz, 2H), 1.33 (t, J=7.2 Hz, 3H). LCMS: 464/466 [M+1].

Compound 031:N2-(3-chloro-4-fluorophenyl)-N8,10-dimethyl-11-oxo-1.3.4.7.8,9,10,11-octahydro-2H-pyrido[4′,3′:3.4]pyrazolo[1,5-a][1,4]diazepine-2,8-dicarboxamide

Step 1.2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-1-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylicacid. To a mixture of ethyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-1-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate(Compound 030, 80.00 mg, 172.45 μmol, 1.00 eq) in MeOH (5.00 mL) and H₂O(1.00 mL) was added NaOH (10.35 mg, 258.68 μmol, 1.50 eq) in oneportion. The mixture was stirred at 30° C. for 12 hours. LCMS showed thereaction was completed. The mixture was concentrated in vacuum andadjust to pH=7 with HCl(1 N). The residue was purified by prep-HPLC(FA)to the title compound (28.00 mg, 63.73 mol, 36.96% yield, 99.2% purity)as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.59 (m, 1H), 7.16-7.23(m, 1H), 7.00-7.10 (m, 1H), 6.58-6.67 (m, 1H), 4.54-4.79 (m, 4H), 3.84(br t, J=5.81 Hz, 3H), 3.58-3.68 (m, 1H), 3.39-3.49 (m, 1H), 3.20 (s,3H), 2.81-2.91 (m, 2H). LCMS: 436/438 [M+1].

Step 2.N2-(3-chloro-4-fluorophenyl)-N8,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,8-dicarboxamide.To a mixture2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylicacid (70.00 mg, 160.61 μmol, 1.00 eq) and methanamine (43.38 mg, 642.44μmol, 4.00 eq, HCl) in DMF (5.00 mL) was added HATU (91.60 mg, 240.92μmol, 1.50 eq) and DIPEA (311.36 mg, 2.41 mmol, 420.76 μL, 15.00 eq) inone portion under N₂. The mixture was stirred at 30° C. for 12 hours.LCMS showed the reaction was completed and the desired product wasdetected. The mixture was poured into water (10 mL), and extracted withethyl acetate (10 mL*2). The combined organic phase was washed withbrine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by prep-HPLC(FA) to affordN2-(3-chloro-4-fluoro-phenyl)-N8,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxamide(25.00 mg, 53.02 μmol, 33.01% yield, 95.2% purity) as white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.54-7.63 (m, 1H), 7.15-7.22 (m, 1H), 7.02-7.10(m, 1H), 6.52-6.58 (m, 1H), 5.82-5.91 (m, 1H), 4.67 (s, 2H), 4.46-4.64(m, 2H), 3.81-3.94 (m, 2H), 3.48-3.67 (m, 2H), 3.22 (s, 3H), 2.87 (d,J=4.77 Hz, 5H). LCMS: 449/451 [M+1].

Compound 032:N2-(3-chloro-4-fluorophenyl)-N8,N8,10-trimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,8-dicarboxamide

To a mixture of2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-1-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylicacid (Compound 030, product from Step 1, 70.00 mg, 160.61 μmol, 1.00 eq)and N-methylmethanamine (65.48 mg, 803.05 μmol, 73.57 μL, 5.00 eq, HCl)in DMF (5.00 mL) was added HATU (91.60 mg, 240.92 μmol, 1.50 eq) andDIPEA (311.36 mg, 2.41 mmol, 420.76 μL, 15.00 eq) in one portion underN2. The mixture was stirred at 30° C. for 12 hours. LCMS showed thereaction was completed and the desired product was detected. The residuewas poured into water (10 mL). The aqueous phase was extracted withethyl acetate (10 mL*2). The combined organic phase was washed withbrine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by prep-HPLC(FA) to affordN2-(3-choro-4-fluoro-phenyl)-N8,N8,10-trimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxamide(30.00 mg, 63.71 mol, 39.67% yield, 98.3% purity) as white solid. 1H NMR(400 MHz, CDCl₃) δ 7.56-7.63 (m, 1H), 7.15-7.22 (m, 1H), 7.02-7.10 (m,1H), 6.51-6.60 (m, 1H), 4.40-4.80 (m, 4H), 3.87 (s, 2H), 3.52-3.70 (m,3H), 3.26 (s, 3H), 3.15 (s, 3H), 3.02 (s, 3H), 2.78-2.91 (m, 2H). LCMS:463/465 [M+1].

Compound 033:N-(3-chloro-4-fluorophenyl)-8-(2-hydroxypropan-2-yl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide

To a mixture of MeMgBr (3 M, 344.90 μL, 6.00 eq) in THF (3.00 mL) wasadded ethyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate(Compound 030, 80.00 mg, 172.45 μmol, 1.00 eq) in THF (3.00 mL) in oneportion at −40° C. under N₂. The mixture was stirred at −40° C. for 30min, then heated to 15° C. and stirred for 2 hours. LCMS showed thereaction was completed. The mixture was poured into sat. NH₄Cl (10 mL)and stirred for 1 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC(FA) to afford the title compound(45.00 mg, 98.91 μmol, 57.36% yield, 98.89% purity) as white solid.LCMS:450/452 [M+1]. 1H NMR (400 MHz, CDCl₃) δ 7.59 (dd, J=2.64, 6.53 Hz,1H), 7.17-7.22 (m, 1H), 7.05 (t, J=8.78 Hz, 1H), 6.62 (s, 1H), 4.69-4.75(m, 1H), 4.52-4.65 (m, 2H), 4.33 (dd, J=7.22, 14.62 Hz, 1H), 3.86 (q,J=5.86 Hz, 2H), 3.43-3.58 (m, 2H), 3.19 (s, 3H), 2.83 (t, J=5.77 Hz,2H), 2.36-2.53 (m, 1H), 1.62 (s, 10H), 1.54 (br s, 1H), 1.31 (d, J=8.66Hz, 6H).

Compound 034:N-(3-chloro-4-fluorophenyl)-8-(1-hydroxyethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.N2-(3-chloro-4-fluoro-phenyl)-N8-methoxy-N8,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxamide.To a mixture of2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylicacid (Compound 030, product from Step 1, 300.00 mg, 688.33 mol, 1.00 eq)and N-methoxymethanamine; hydrochloride (268.56 mg, 2.75 mmol, 4.00 eq)in DMF (5.00 mL) was added HATU (392.58 mg, 1.03 mmol, 1.50 eq) andDIPEA (1.33 g, 10.32 mmol, 1.80 mL, 15.00 eq) in one portion under N₂.The mixture was stirred at 30° C. for 5 hours. TLC(Dichloromethane:Methanol=10:1) showed the reaction was completed. Themixture was poured into water (15 mL) and extracted with ethyl acetate(20 mL*2). The combined organic phase was washed with brine (10 mL*2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography(Dichloromethane:Methanol=50:1,20:1) to afford the title compound(310.00 mg, 586.47 μmol, 85.20% yield, 90.6% purity) as white solid.LCMS: 479/481 [M+1].

Step 2.8-acetyl-N-(3-chloro-4-fluoro-phenyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a mixture of MeMgBr (3 M, 1.11 mL, 20.00 eq) in THF (3.00 mL) wasaddedN2-(3-chloro-4-fluoro-phenyl)-N8-methoxy-N8,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxamide(80.00 mg, 167.05 μmol, 1.00 eq) in THF (1.00 mL) drop-wise at 0° C.under N₂. The mixture was heated to 30° C. and stirred for 14 hours. TLC(Ethyl acetate: Methanol=20:1) showed the reaction was completed. Themixture was poured into sat. NH₄Cl (20 mL) and extracted with ethylacetate (15 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-TLC (Ethyl acetate: Methanol=20:1) toafford the title compound (25.00 mg, 54.16 μmol, 32.42% yield, 94%purity) as yellow solid. LCMS: 434/436 [M+1].

Step 3.N-(3-chloro-4-fluorophenyl)-8-(1-hydroxyethyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. To a mixture of8-acetyl-N-(3-chloro-4-fluoro-phenyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(25.00 mg, 57.62 μmol, 1.00 eq) in EtOH (3.00 mL) was added NaBH₄ (3.27mg, 86.43 μmol, 1.50 eq) in one portion at 0° C. under N₂. The mixturewas stirred at 0° C. for 2 hours. LCMS showed the reaction wascompleted. The residue was poured into water (10 mL) and extracted withethyl acetate (10 mL*2). The combined organic phase was washed withbrine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by prep-HPLC(FA) to afford the titlecompound (15.00 mg, 34.31 μmol, 59.55% yield, 99.7% purity) as whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J=6.43 Hz, 1H), 7.17-7.25 (m,1H), 7.05 (t, J=8.90 Hz, 1H), 6.60 (br d, J=4.03 Hz, 1H), 4.56-4.73 (m,2H), 4.31-4.44 (m, 1H), 4.10 (dd, J=6.97, 14.31 Hz, 1H), 3.88-3.92 (m,1H), 3.77-3.88 (m, 1H), 3.75-3.95 (m, 1H), 3.63 (dd, J=6.05, 14.73 Hz,1H), 3.48 (dd, J=5.14, 14.92 Hz, 1H), 3.31-3.38 (m, 1H), 3.19 (d, J=3.67Hz, 3H), 2.84 (t, J=5.75 Hz, 2H), 2.36-2.47 (m, 1H), 1.61 (br s, 12H),1.31 (dd, J=6.30, 11.80 Hz, 3H). LCMS:436/438 [M+1].

Compound 035:N-(3-chloro-4-fluorophenvl)-8-(1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.N-(3-chloro-4-fluoro-phenyl)-10-methyl-11-oxo-8-propanoyl-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a mixture of bromo(ethyl)magnesium (3 M, 1.39 mL, 20.00 eq) in THF(3.00 mL) was addedN2-(3-chloro-4-fluoro-phenyl)-N8-methoxy-N8,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxamide(Compound 034, product from Step 1, 100.00 mg, 208.81 mol, 1.00 eq) inTHF (2.00 mL) drop-wise at 0° C. under N₂. The mixture was heated to 30°C. and stirred for 4 hours. LCMS and TLC (Ethyl acetate: Methanol=20:1)showed the reaction was completed. The mixture was poured into water (10mL) and stirred for 2 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-TLC (Ethyl acetate: Methanol=20:1) toafford the title compound (30.00 mg, 66.98 μmol, 32.08% yield, 100%purity) as yellow solid. LCMS: 448/450 [M+1].

Step 2.N-(3-chloro-4-fluorophenyl)-8-(1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a mixture ofN-(3-chloro-4-fluoro-phenyl)-10-methyl-11-oxo-8-propanoyl-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(30.00 mg, 66.98 μmol, 1.00 eq) in EtOH (3.00 mL) was added NaBH₄ (3.80mg, 100.47 μmol, 1.50 eq) in one portion at 0° C. under N₂. The mixturewas stirred at 20° C. for 2 hours. LCMS showed the reaction wascompleted. The residue was poured into water (10 mL). The aqueous phasewas extracted with ethyl acetate (10 mL*2). The combined organic phasewas washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by prep-HPLC(FA) toafford the title compound (25.00 mg, 52.90 mol, 78.98% yield, 95.2%purity) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (dd, J=1.96, 6.60Hz, 1H), 7.17-7.25 (m, 1H), 7.05 (t, J=8.80 Hz, 1H), 6.62 (br d, J=3.79Hz, 1H), 4.57-4.73 (m, 3H), 4.29-4.44 (m, 1H), 4.15 (br d, J=7.09 Hz,1H), 3.79-3.92 (m, 2H), 3.64 (br dd, J=5.87, 15.04 Hz, 1H), 3.48 (br d,J=5.14 Hz, 1H), 3.37 (d, J=7.46 Hz, 1H), 3.19 (d, J=2.08 Hz, 3H), 2.84(br t, J=5.50 Hz, 2H), 2.43-2.53 (m, 1H), 1.85-1.99 (m, 1H), 1.40-1.57(m, 2H), 0.99-1.07 (m, 3H). LCMS: 450/452 [M+1].

Compound 036:N-(3-chloro-4-fluorophenyl)-8-(cyclopropyl(hydroxy)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.N-(3-chloro-4-fluoro-phenyl)-8-(cyclopropanecarbonyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a mixture of bromo(cyclopropyl)magnesium (0.5 M, 7.52 mL, 15.00 eq)in THF (3.00 mL) was addedN2-(3-chloro-4-fluoro-phenyl)-N8-methoxy-N8,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxamide(Compound 034, product from Step 1, 120.00 mg, 250.57 mol, 1.00 eq) inTHF (2.00 mL) drop-wise at 0° C. under N₂. The mixture was heated to 15°C. and stirred for 14 hours. LCMS and TLC (Ethyl acetate: Methanol=20:1)showed the starting material:desired product=2:3. The mixture was pouredinto 1N HCl (10 mL) and stirred for 2 min. The aqueous phase wasextracted with ethyl acetate (10 mL*2). The combined organic phase waswashed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by prep-TLC (Ethylacetate: Methanol=20:1) to afford the title compound (50.00 mg, 101.11mol, 40.35% yield, 93% purity) as yellow solid. LCMS: 460/462 [M+1].

Step 2.N-(3-chloro-4-fluorophenyl)-8-(cyclopropyl(hydroxy)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a mixture ofN-(3-chloro-4-fluoro-phenyl)-8-(cyclopropanecarbonyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(50.00 mg, 108.72 μmol, 1.00 eq) in EtOH (3.00 mL) was added NaBH₄ (6.17mg, 163.08 μmol, 1.50 eq) in one portion at 0° C. under N₂. The mixturewas stirred at 20° C. for 2 hours. LCMS showed the reaction wascompleted. The residue was poured into water (10 mL) and extracted withethyl acetate (10 mL*2). The combined organic phase was washed withbrine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by prep-HPLC(FA) to afford the titlecompound (46.00 mg, 98.29 μmol, 90.41% yield, 98.7% purity) as whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (dd, J=2.32, 6.48 Hz, 1 bH),7.15-7.23 (m, 1H), 7.05 (t, J=8.80 Hz, 1H), 6.61 (br s, 1H), 4.59-4.74(m, 3H), 4.44-4.54 (m, 1H), 4.24-4.42 (m, 1H), 3.78-3.92 (m, 2H),3.60-3.68 (m, 1H), 3.45-3.58 (m, 1H), 3.33-3.43 (m, 1H), 3.19 (d, J=5.50Hz, 2H), 3.13-3.25 (m, 1H), 2.79-2.90 (m, 2H), 2.79-2.91 (m, 1H), 2.65(br d, J=6.97 Hz, 1H), 1.74-1.98 (m, 1H), 0.90-1.06 (m, 1H), 0.57-0.78(m, 2H), 0.40-0.51 (m, 1H), 0.32 (br dd, J=3.55, 7.95 Hz, 2H). LCMS:462/464 [M+1].

Compound 037:N-(3-chloro-4-fluorophenyl)-8-(difluoromethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.N-(3-chloro-4-fluoro-phenyl)-8-(hydroxymethyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a mixture of ethyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate(Compound 030, 500.00 mg, 1.08 mmol, 1.00 eq) in THF (5.00 mL) was addedLiAlH₄ (61.48 mg, 1.62 mmol, 1.50 eq) in one portion at −40° C. underN₂. The mixture was stirred at −40° C. for 30 min, then heated to 0° C.and stirred for 2 hours. TLC (Dichloromethane:Methanol=10:1) showed thereaction was completed. The mixture was poured into HCl (1 N, 10 mL) andstirred for 1 min. The resulting was extracted with ethyl acetate (20mL*2). The combined organic phase was washed with brine (10 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by silica gel chromatography(Dichloromethane:Methanol=100:1-20:1) to afford the title compound(330.00 mg, 775.38 mol, 71.79% yield, 99.12% purity) as yellow solid.LCMS: 422/424 [M+1].

Step 2.N-(3-chloro-4-fluoro-phenyl)-8-formyl-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a mixture ofN-(3-chloro-4-fluoro-phenyl)-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(50.00 mg, 118.53 mol, 1.00 eq) in DCM (3.00 mL) was added Dess-Martin(75.41 mg, 177.79 μmol, 55.04 μL, 1.50 eq) in one portion at 0° C. underN₂. The mixture was stirred at 30° C. for 12 hours. LCMS showed thereaction was completed. The mixture was concentrated in vacuum. Theresidue was purified by silica gel chromatography (Ethyl acetate) toafford the title compound (40.00 mg, 43.83 μmol, 36.97% yield, 46%purity) as yellow solid.

Step 3.N-(3-chloro-4-fluorophenyl)-8-(difluoromethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. To a mixture ofN-(3-chloro-4-fluoro-phenyl)-8-formyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(40.00 mg, 95.27 μmol, 1.00 eq) in DCM (4.00 mL) was added DAST (76.78mg, 476.35 μmol, 62.93 μL, 5.00 eq) in one portion at −78° C. under N₂.The mixture was stirred at −78° C. for 2 hours, then heated to 20° C.and stirred for 12 hours. LCMS showed the reaction was completed. Themixture was poured into water (10 mL) and stirred for 2 min. The aqueousphase was extracted with DCM (10 mL*2). The combined organic phase waswashed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by prep-HPLC(FA) toafford the title compound (15.00 mg, 33.58 μmol, 35.24% yield, 98.9%purity) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, J=2.63, 6.54Hz, 1H), 7.17-7.26 (m, 1H), 7.06 (t, J=8.74 Hz, 1H), 6.57 (br s, 1H),5.72-6.06 (m, 1H), 4.63-4.72 (m, 2H), 4.52 (dd, J=7.15, 14.49 Hz, 1H),4.40 (dd, J=6.91, 14.61 Hz, 1H), 3.85 (q, J=5.42 Hz, 2H), 3.55 (dq,J=5.81, 15.39 Hz, 2H), 3.19 (s, 3H), 2.80-2.97 (m, 3H), 1.60 (br s,11H). LCMS: 442/444 [M+1].

Compound 038:N-(3-chloro-4-fluorophenvl)-10-(2,2-difluoroethyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl10-(2,2-difluoroethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 5, 100.00 mg, 326.41 μmol, 1.00 eq) in DMF (3.00 mL) wasadded NaH (19.58 mg, 489.61 μmol, 60% purity, 1.50 eq) at 0° C. underN₂. After stirred at 0° C. for 30 minutes, 2,2-difluoroethyltrifluoromethanesulfonate (349.44 mg, 1.63 mmol, 5.00 eq) was added. Thereaction mixture was stirred at 15° C. for one hour. LCMS showedcompound 5 was consumed completely and about 65% of desired compound wasdetected. The reaction was quenched with water (30 mL) and thenextracted with EtOAc (50 mL*3). The combined organic phase was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by silica gel chromatography to afford the title compound(64.00 mg, 172.79.mol, 52.94% yield) was obtained as yellow oil. LCMS:371 [M+1].

Step 2.10-(2,2-difluoroethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl10-(2,2-difluoroethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (62.00 mg, 167.39 μmol,1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL,80.69 eq), the reaction mixture was stirred at 20° C. for one hour. TLCindicated compound 6 was consumed completely, and one major new spotwith larger polarity was detected. The solvent was removed on a rotaryevaporator to afford the title compound (64.00 mg, crude, TFA) wasobtained as yellow oil, which was used in next step directly withoutfurther purification.

Step 3.N-(3-chloro-4-fluorophenvl)-10-(2,2-difluoroethyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a mixture of10-(2,2-difluoroethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (64.00 mg, 166.54 μmol, 1.00 eq, TFA) in DCM(5.00 mL) was added TEA (67.41 mg, 666.15 μmol, 92.34 μL, 4.00 eq),followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (44.24 mg,166.54 μmol, 1.00 eq), the reaction mixture was stirred at 20° C. for 16hours. LCMS showed a main peak with desired MS was detected. The mixturewas extracted with DCM (50 mL*2) and water (30 mL), the organic phasewas dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC(FA) to afford the title compound(72.00 mg, 161.20 μmol, 96.79% yield, 98.92% purity) was obtained aswhite solid. ¹H NMR (400 MHz, CDCl₃) δ=7.55-7.57 (dd, J=6.48, 2.69 Hz,1H) 7.18-7.20 (m, 1H) 7.03-7.07 (m, 1H) 6.54 (s, 1H) 5.89-6.18 (m, 1H)4.67 (s, 2H) 4.39-4.43 (t, J=6.91 Hz, 2H) 3.83-3.92 (m, 4H) 3.57-3.61(t, J=6.24 Hz, 2H) 2.83-2.86 (t, J=5.75 Hz, 2H) 2.32-2.38 (m, J=6.57 Hz,2H). LCMS: 442/444 [M+1]

Compound 039:N-(3-chloro-4-fluorophenvl)-9,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.9,10-dimethyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepin-11-one.To a mixture of tert-butyl9,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2-carboxylate(Intermediate 8, 66.00 mg, 197.36 μmol, 1.00 eq) in DCM (2.00 mL) wasadded TFA (1.54 g, 13.51 mmol, 1.00 mL, 68.44 eq) in one portion underN₂. The mixture was stirred at 15° C. for 2 hours. TLC(Dichloromethane:Methanol=10:1) showed the reaction was completed. Themixture was concentrated in vacuum to afford the title compound (68.74mg, 197.35 μmol, 100.00% yield, TFA) as yellow oil.

Step 2.N-(3-chloro-4-fluorophenyl)-9,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a mixture of9,10-dimethyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepin-11-one(68.74 mg, 197.35 μmol, 1.00 eq, TFA) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (52.43 mg, 197.35 μmol, 1.00 eq)in DCM (6.00 mL) was added TEA (199.70 mg, 1.97 mmol, 273.56 μL, 10.00eq) under N₂. The mixture was stirred at 25° C. for 10 hours. LCMSshowed the reaction was completed. The residue was poured into water (10mL) and stirred for 2 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC(FA) to afford the title compound(46.00 mg, 112.20 mol, 56.85% yield, 98.99% purity) as white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.57-7.61 (m, 1H), 7.16-7.22 (m, 1H), 7.01-7.09(m, 1H), 6.52-6.59 (m, 1H), 4.71 (s, 2H), 4.44-4.54 (m, 1H), 4.31-4.43(m, 1H), 3.84 (s, 3H), 3.14 (s, 3H), 2.79-2.89 (m, 2H), 2.36-2.51 (m,1H), 2.11-2.27 (m, 1H), 1.35 (d, J=6.97 Hz, 3H). LCMS: 406/408 [M+1].

Compound 040: methyl2-((3-chloro-4-fluorophenyl)carbamoyl)-9-methyl-10-oxo-1,2,3,4,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8-carboxylate

Step 1. methyl 9-methyl-10-oxo-1,2,3,4-tetrahydropyrido[2,3]pyrazolo[2,4-b]pyrazine-8-carboxylate. A mixture of2-tert-butyl8-methyl8-methoxy-9-methyl-10-oxo-1,3,4,7-tetrahydropyrido[2,3]pyrazolo[2,4-c]pyrazine-2,8-dicarboxylate (Intermediate 9,20.00 mg, 50.71 μmol, 1.00 eq) in HCl/dioxane (4 M, 20.00 mL, 1577.60eq) was stirred at 20° C. for 2 hours. LCMS showed the reaction wascompleted. The residue was concentrated in vacuum to afford the titlecompound (15.15 mg, 50.71 μmol, 100.00% yield, HCl) as yellow solid.LCMS: 263 [M+1].

Step 2. methyl2-((3-chloro-4-fluorophenvl)carbamoyl)-9-methyl-10-oxo-1,2,3,4,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8-carboxylate.To a mixture of methyl9-methyl-10-oxo-1,2,3,4-tetrahydropyrido[2,3]pyrazolo[2,4-b]pyrazine-8-carboxylate (15.15 mg, 50.71 μmol, 1.00 eq, HCl) andphenyl N-(3-chloro-4-fluoro-phenyl)carbamate (13.47 mg, 50.71 μmol, 1.00eq) in DCM (4.00 mL) was added TEA (51.32 mg, 507.15 μmol, 70.30 μL,10.00 eq) under N₂. The mixture was stirred at 25° C. for 10 hours. LCMSshowed the reaction was completed. The residue was poured into water (10mL) and stirred for 2 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC (FA) to afford the title compound(15.00 mg, 32.43 μmol, 63.96% yield, 93.8% purity) as white solid. ¹HNMR (400 MHz, CDCl₃) 8.20 (s, 1H), 7.56-7.63 (m, 1H), 7.14-7.24 (m, 1H),7.02-7.12 (m, 1H), 6.55 (s, 1H), 4.93 (s, 2H), 3.95 (s, 3H), 3.92 (s,1H), 3.75 (s, 3H), 2.97-3.05 (m, 1H). LCMS: 434 [M+1].

Compound 041:N-(3-chloro-4-fluorophenvl)-8-(hydroxymethyl)-9-methyl-10-oxo-3,4,9,10-tetrahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide

To a mixture of methyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-9-methyl-10-oxo-3,4-dihydro-1H-pyrido[2,3]pyrazolo[2,4-b]pyrazine-8-carboxylate(Compound 040, 30.00 mg, 69.15 μmol, 1.00 eq) in THF (2.00 mL) was addedLiBH₄ (2.26 mg, 103.73 μmol, 1.50 eq) in one portion at 0° C. under N₂.The mixture was stirred at 0° C. for 1 hour, then heated to 20° C. andstirred for 2 hours. LCMS showed the reaction was completed. Thereaction was quenched with NH₄Cl (5 mL). The aqueous phase was extractedwith ethyl acetate (10 mL*2). The combined organic phase was washed withbrine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by prep-HPLC(FA) to afford the titlecompound (18.00 mg, 44.18 μmol, 63.89% yield, 99.6% purity) as whitesolid. ¹H NMR (400 MHz, METHANOL-d₄) 7.60 (s, 2H), 7.26-7.39 (m, 1H),7.06-7.20 (m, 1H), 4.94 (s, 2H), 4.56 (s, 2H), 3.82-3.93 (m, 2H), 3.59(s, 3H), 2.89-2.98 (m, 2H). LCMS: 406 [M+1].

Compound 042:2-((3-chloro-4-fluorophenyl)carbamoyl)-9-methyl-10-oxo-1,2,3,4,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8-carboxylicAcid

To a mixture of methyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-9-methyl-10-oxo-3,4-dihydro-1H-pyrido[2,3]pyrazolo[2,4-b]pyrazine-8-carboxylate(Compound 040, 36.00 mg, 82.98 μmol, 1.00 eq) in MeOH (4.00 mL) and H₂O(1.00 mL) was added NaOH (6.64 mg, 165.96 μmol, 2.00 eq) in one portionunder N₂. The mixture was stirred at 30° C. for 5 hours. LCMS showed thereaction was completed. The residue was adjust to pH=7 with 1N HCl andconcentrated in vacuum. The residue was purified by prep-HPLC(HCl) toafford the title compound (8.00 mg, 18.77 μmol, 22.62% yield, 98.5%purity) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) 7.81-7.94 (m, 1H),7.51-7.72 (m, 1H), 7.22-7.38 (m, 1H), 7.04-7.19 (m, 1H), 4.94 (s, 2H),3.82-3.91 (m, 2H), 3.67 (s, 3H), 2.89-3.01 (m, 2H). LCMS: 420 [M+1].

Compound 043: methyl2-((3-chloro-4-fluorophenvl)carbamoyl)-9-methyl-10-oxo-1,2,3,4,7,8,9,10-octahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8-carboxylate

Step 1. methyl9-methyl-10-oxo-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-c]pyrazine-8-carboxylate.To a solution of methyl9-methyl-10-oxo-1,2,3,4-tetrahydropyrido[2,3]pyrazolo[2,4-b]pyrazine-8-carboxylate(Intermediate 10, 10.00 mg, 33.48 μmol, 1.00 eq, HCl) in AcOH (2.00 mL)was added Pd/C (4.00 mg, 33.48 μmol, 1.00 eq) under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (50 psi) at 40° C. for 12 hours. LCMS showed littleDesired product was detected. The reaction mixture was filtered and thefilter was concentrated to afford the title compound (10.86 mg, crude,HOAC) as yellow oil. LCMS: 265 [M+1].

Step 2. methyl2-((3-chloro-4-fluorophenvl)carbamoyl)-9-methyl-10-oxo-1,2,3,4,7,8,9,10-octahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8-carboxylate.To a mixture of methyl9-methyl-10-oxo-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-c]pyrazine-8-carboxylate(15.57 mg, 41.16 μmol, 1.00 eq, TFA) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (10.93 mg, 41.16 μmol, 1.00 eq) inDCM (4.00 mL) was added TEA (41.65 mg, 411.58 μmol, 57.05 μL, 10.00 eq)under N₂. The mixture was stirred at 25° C. for 10 hours. LCMS and TLC(Dichloromethane: Methanol=10:1) showed the reaction was completed. Theresidue was poured into water (10 mL) and stirred for 2 min. The aqueousphase was extracted with ethyl acetate (10 mL*2). The combined organicphase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-TLC (Dichloromethane:Methanol=10:1) to afford the title compound(16.00 mg, 35.76 μmol, 86.87% yield, 97.4% purity) as white solid. ¹HNMR (400 MHz, CDCl₃) 7.58-7.65 (m, 1H), 7.17-7.24 (m, 1H), 7.00-7.11 (m,1H), 6.64-6.72 (m, 1H), 4.65-4.90 (m, 3H), 4.50-4.61 (m, 1H), 4.32-4.39(m, 1H), 3.83-3.91 (m, 2H), 3.79 (s, 3H), 3.17 (s, 3H), 2.79-2.90 (m,2H). LCMS: 436 [M+1].

Compound 044:N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-9-methyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide

To a mixture of methyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-9-methyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-8-carboxylate(Compound 043, 13.00 mg, 29.83 μmol, 1.00 eq) in THF (2.00 mL) was addedLiBH₄ (3.25 mg, 149.14 μmol, 5.00 eq) in one portion at 0° C. under N₂.The mixture was stirred at 0° C. for 1 hours, then heated to 20° C. andstirred for 2 hours. LCMS showed the reaction was completed. Thereaction was quenched with NH₄Cl (5 mL), the aqueous phase was extractedwith ethyl acetate (10 mL*2). The combined organic phase was washed withbrine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by prep-HPLC(FA) to afford the titlecompound (9.00 mg, 21.94 mol, 73.54% yield, 99.4% purity) as whitesolid. ¹H NMR (400 MHz, METHANOL-d₄) 7.55-7.62 (m, 1H), 7.26-7.33 (m,1H), 7.08-7.19 (m, 1H), 4.75 (d, J=2.32 Hz, 2H), 4.35-4.56 (m, 2H),3.65-3.93 (m, 4H), 3.43-3.53 (m, 1H), 3.18 (s, 3H), 2.82 (s, 2H). LCMS:408 [M+1].

Compound 045:N-(3-chloro-4-fluorophenvl)-9-methyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3.4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide

Step 1. 9-methyl-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-b]pyrazin-10-one. To a mixture of tert-butyl9-methyl-10-oxo-3,4,7,8-tetrahydro-H-pyrido[2,3]pyrazolo[2,4-b]pyrazine-2-carboxylate (Intermediate 6, 70.00 mg, 228.49μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00mL, 59.11 eq) in one portion under N₂. The mixture was stirred at 20° C.for 2 hours. TLC (Dichloromethane:Methanol=10:1) showed the reaction wascompleted. The mixture was concentrated in vacuum to afford the titlecompound (73.18 mg, 228.49 μmol, 100.00% yield, TFA) as yellow oil.

Step 2.N-(3-chloro-4-fluorophenyl)-9-methyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide.To a mixture of9-methyl-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-b]pyrazin-10-one(73.18 mg, 228.49 μmol, 1.00 eq, TFA) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (60.70 mg, 228.49 μmol, 1.00 eq)in DCM (6.00 mL) was added TEA (231.21 mg, 2.28 mmol, 316.73 μL, 10.00eq) under N₂. The mixture was stirred at 25° C. for 10 hours. LCMSshowed the reaction was completed. The residue was poured into water (10mL) and stirred for 2 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC(FA) to afford the title compound(47.00 mg, 124.16 mol, 54.34% yield, 99.8% purity) as white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.56-7.63 (m, 1H), 7.14-7.24 (m, 1H), 7.01-7.11(m, 1H), 6.61 (s, 1H), 4.74 (s, 2H), 4.32-4.44 (m, 2H), 3.87 (t, J=5.75Hz, 2H), 3.74-3.81 (m, 2H), 3.14 (s, 3H), 2.86 (t, J=5.75 Hz, 2H). LCMS:378/380 [M+1].

Compound 046:N-(3-chloro-4-fluorophenyl)-10-methyl-1,3,4.7.8,9,10,11-octahydro-2H-pyrido[4′,3′:3.4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl1,3,4.7.8,9,10,11-octahydropyrido[2,3]pyrazolo[2,4-a][1,4]diazepine-2-carboxylate.To a solution of tert-butyl11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (Intermediate 5, 180.00 mg, 587.54μmol, 1.00 eq) in toluene (3.00 mL) was added Red-Al® (503.96 mg, 1.76mmol, 503.96 μL, 70% purity, 3.00 eq). The mixture was stirred at 0° C.for 30 min. Additional 0.05 mL of aliquots of the Red-Al® (sodiumbis(2-methoxyethoxy)aluminum dihydride) solution was added every 30minutes for four times. TLC (EA:MeOH=10:1) and LCMS showed tert-butyl11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate nearly consumed and 60% desiredproduct appeared. The mixture was quenched with 40% NaOH (5 mL), dilutedwith 50 mL of DCM:MeOH (10:1) and filtrated. The filtrate wasconcentrated in vacuum. The residue was purified by columnchromatography (EtOAc:MeOH, 0%10%) to afford the title compound (100.00mg, 249.68 μmol, 42.49% yield, 73% purity) as brown oil.

Step 2. tert-butyl10-methyl-3,4,7,8,9,11-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-a][1,4]diazepine-2-carboxylate.To a solution of tert-butyl1,3,4,7,8,9,10,11-octahydropyrido[2,3]pyrazolo[2,4-a][1,4]diazepine-2-carboxylate(60.00 mg, 205.21 μmol, 1.00 eq) and HCHO (166.55 mg, 2.05 mmol, 152.80μL, 37% purity, 10.00 eq) in MeOH (5.00 mL) was added HOAc (1.23 mg,20.52 μmol, 1.17 μL, 0.10 eq). The mixture was stirred at 20° C. for 0.5hr. Then NaBH₃CN (51.58 mg, 820.85 mol, 4.00 eq) was added. The mixturewas stirred at 20° C. for 16 hr. TLC (EtOAc:MeOH=10:1) showed one mainspot appeared. The mixture was concentrated in vacuum. The residue wasextracted with EtOAc (20 mL*2) and H₂O (10 mL). The combined organiclayer was dried over Na₂SO₄, filtrated. The filtrate was concentrated invacuum to afford the title compound (62.00 mg, crude) as brown oil.

Step 3.10-methyl-1,2,3,4,7,8,9,11-octahydropyrido[2,3]pyrazolo[2,4-a][1,4]diazepine.To a solution of tert-butyl10-methyl-3,4,7,8,9,11-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-a][1,4]diazepine-2-carboxylate (80.00 mg, 261.10 μmol, 1.00 eq) inDCM (4.00 mL) was added TFA (6.16 g, 54.03 mmol, 4.00 mL, 206.92 eq).The mixture was stirred at 20° C. for 2 hr. TLC (EA:MeOH=10:1) showedCompound 3 consumed. The mixture was concentrated in vacuum to affordthe title compound (85.00 mg, crude, TFA) as brown oil.

Step 4.N-(3-chloro-4-fluorophenvl)-10-methyl-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of10-methyl-1,2,3,4,7,8,9,11-octahydropyrido[2,3]pyrazolo[2,4-a][1,4]diazepine(85.00 mg, 265.37 μmol, 1.00 eq, TFA) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (70.50 mg, 265.37 μmol, 1.00 eq)in DCM (3.00 mL) was added TEA (134.26 mg, 1.33 mmol, 183.92 μL, 5.00eq). The mixture was heated to 20° C. for 16 hr. LCMS showed one mainpeak with desired Ms. The mixture was concentrated in vacuum. Theresidue was purified by prep-HPLC(FA), followed by prep-TLC(DCM:MeOH=10:1) and prep-HPLC(Base) to afford the title compound (15.00mg, 39.58 μmol, 14.92% yield, 99.7% purity) as white solid. ¹H NMR (400MHz, CDCl₃) δ=7.46 (dd, J=2.69, 6.48 Hz, 1H), 7.07-7.16 (m, 1H),6.90-7.02 (m, 1H), 6.34 (s, 1H), 4.41 (s, 2H), 4.15-4.25 (m, 2H), 3.67(t, J=5.81 Hz, 2H), 3.57 (s, 2H), 2.86-2.99 (m, 2H), 2.74 (t, J=5.75 Hz,2H), 2.30 (s, 3H), 1.82 (br t, J=4.95 Hz, 2H). LCMS [M+1]: 378.

Compound 047:N-(3-chloro-4-fluoro-phenyl)-8-(2-cyclopropyl-1-hydroxy-ethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide

Step 1.8-but-3-enoyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of allyl(bromo)magnesium (1 M, 2.09 mL, 2.00 eq) in THF(10.00 mL) was added a solution of tert-butyl8-[methoxy(methyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 11, 500.00 mg, 1.04 mmol, 1.00 eq) in THF (10.00 mL)drop-wise at −30° C. over a period of 10 mins under N₂ and stirred for 1hour. TLC indicated about 35% starting material remained, then anotherbatch of allyl(bromo)magnesium (1 M, 2.09 mL, 2.00 eq) was added intothe mixture drop-wise at −30° C. over a period of 10 mins and stirredfor 1 hour. TLC indicated the starting material was completely consumed,one new spot was detected. The reaction mixture was poured into 1N HCl(50 ml) at 0° C. and stirred for 10 min. The aqueous phase was extractedwith ethyl acetate (10 mL*2). The combined organic layers was washedwith brine (10 mL*1), dried over with Na₂SO₄, filtered and concentratedunder reduced pressure to afford the title compound (170.00 mg, crude)as yellow solid, which was used into the next step without furtherpurification.

Step 2. tert-butyl8-(1-hydroxybut-3-enyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a mixture of tert-butyl8-but-3-enoyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (300.00 mg,772.28 μmol, 1.00 eq) in MeOH (10.00 mL) was added NaBH₄ (58.43 mg, 1.54mmol, 2.00 eq) in one portion at 0° C. The mixture was stirred at 25° C.for 2 hours. TLC indicated the starting material was consumed completelyand one new spot formed. The reaction mixture was filtered andconcentrated in vacuum, then diluted with H₂O (20 mL) and extracted withEtOAc (10*3 mL). The combined organic layers was washed with brine (15mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/1 to 0:1) to afford the title compound(182.00 mg, 466.09 mol, 60.35% yield) as yellow oil.

Step 3. tert-butyl8-(2-cyclopropyl-1-hydroxy-ethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a stirred suspension of ZnEt₂ (1 M, 1.23 mL, 12.00 eq) in toluene(8.00 mL) was added CH₂ICl (438.60 mg, 2.49 mmol, 24.27 eq) slowlydrop-wise at −20° C. The resulting mixture was stirred for 1 h and addeda solution of tert-butyl8-(1-hydroxybut-3-enyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(40.00 mg, 102.44 μmol, 1.00 eq) in toluene (2.00 mL) drop-wise at −20°C. The resulting mixture was stirred at −20° C. for 12 h. TLC indicatedone major new spot with larger polarity was detected. LC-MS showed thestarting material was consumed completely and one main peak with desiredMS was detected. The reaction was cooled to 0° C. and quenched withsaturated solution of NH₄Cl (25 mL) and extracted with EtOAc (2*20 mL),dried over sodium sulfate and evaporated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, Petroleum ether: Ethylacetate=1:10) to afford the title compound (30.00 mg, 74.17 μmol, 72.40%yield) as white solid. LCMS: 405[M+1].

Step 4.8-(2-cyclopropyl-1-hydroxy-ethyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one. To a solution of tert-butyl8-(2-cyclopropyl-1-hydroxy-ethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(30.00 mg, 74.17 mol, 1.00 eq) in DCM (8.00 mL) was added TFA (6.16 g,54.03 mmol, 4.00 mL, 728.40 eq). The mixture was stirred at 30° C. for 1h. TLC and LCMS indicated the starting material was consumed completelyand one main peak with desired MS was detected. The mixture wasconcentrated under reduced pressure to afford the title compound (50.00mg, crude, TFA) as yellow oil. The residue was used into the next stepwithout further purification.

LCMS: 305[M+1].

Step 5.N-(3-chloro-4-fluoro-phenyl)-8-(2-cyclopropyl-1-hydroxy-ethyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a solution of8-(2-cyclopropyl-1-hydroxy-ethyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(18.00 mg, 43.02 μmol, 1.00 eq, TFA) and TEA (21.77 mg, 215.10 μmol,29.82 μL, 5.00 eq) in DCM (8.00 mL) was added phenylN-(3-chloro-4-fluoro-phenyl)carbamate (13.71 mg, 51.62 μmol, 1.20 eq)with stirring at 30° C. for 1 h. LCMS indicated the desired MS. Themixture was directly evaporated in vacuo and purified by prep-HPLC(FA)to afford the title compound (2.49 mg, 5.23 μmol, 12.16% yield) as whitesolid. LCMS: 476[M+1]. ¹H NMR (400 MHz, CDCl₃) δ H NMR (400 MHz, CDCl₃)δ 7.59 (dd, J=2.57, 6.60 Hz, 1H), 7.15-7.25 (m, 1H), 7.00-7.11 (m, 1H),6.60 (br d, J=4.40 Hz, 1H), 4.61-4.72 (m, 2.5H), 4.38-4.39 (m, 1H),4.10-4.16 (m, 0.5H), 3.81-3.87 (m, 3H), 3.48-3.62 (m, 1H), 3.35-3.38 (m,1H), 3.18 (s, 3H), 2.82-2.84 (m, 2H), 2.51-2.53 (m, 1H), 2.11-2.13 (m,1H), 1.35-1.42 (m, 2H), 0.75-0.81 (m, 1H), 0.53-0.61 (m, 2H), 0.10-0.216(m, 2H).

Compound 048: (3R)—N-(3-chloro-4-fluorophenyl)-10-(2-hydroxy-2-methylpropyl)-3-methyl-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl(3R)-10-(2-methoxy-2-oxo-ethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl(3R)-3-methyl-11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (Intermediate 12,100.00 mg, 312.12 μmol, 1.00 eq) in THF (5.00 mL) was added NaH (24.97mg, 624.24 μmol, 60% purity, 2.00 eq) at 0° C. with stirring for 0.5 hunder N₂. Then followed by methyl 2-bromoacetate (62.07 mg, 405.76 μmol,38.32 μL, 1.30 eq). The mixture was stirred at 20° C. for 2 h. TLC (PE:EtOAc=1:3) showed that the tert-butyl(3R)-3-methyl-11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate was consumed completelyand one main new spot formed. The mixture was quenched with 10 mL ofice-water and extracted with EtOAc (20 mL*3). The organic phase waswashed with brine (15 mL*1), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc=1:3) to obtain the title compound (116.00 mg, 280.29 μmol, 89.80%yield) as white solid.

Step 2.tert-butyl(3R)-10-(2-hydroxy-2-methyl-propyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a mixture of MeMgBr (3 M, 1.02 mL, 10.00 eq) in THF (5.00 mL) wasadded a solution of tert-butyl(3R)-10-(2-methoxy-2-oxo-ethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(120.00 mg, 305.77 μmol, 1.00 eq) in THF (3.00 mL) in one portion at 0°C. under N₂. TLC showed that the tert-butyl(3R)-10-(2-methoxy-2-oxo-ethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylatewas consumed completely and one new spot formed. The mixture was stirredat 0° C. for 0.5 h, then warmed to 20° C. and stirred for 2 h. Themixture was quenched with saturated NH₄Cl aqueous solution and extractedwith EtOAc (20 mL*3). The organic phase was washed with brine (20 mL*1),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by prep-TLC and further purified by prep-HPLC (FA)to obtain the title compound (40 mg, 93% purity) as off-white oil. ¹HNMR (400 MHz, CDCl₃) δ=4.76-5.07 (m, 2H), 4.29-4.50 (m, 2H), 4.07-4.21(m, 1H), 3.64-3.70 (m, 1H), 3.47-3.62 (m, 3H), 2.92 (br dd, J=5.90,15.81 Hz, 1H), 2.56 (br d, J=15.81 Hz, 2H), 2.25-2.42 (m, 2H), 2.15-2.23(m, 1H), 1.47 (s, 9H), 1.28 (d, J=4.64 Hz, 6H), 1.12 (d, J=6.90 Hz, 3H).

Step 3.(3R)-10-(2-hydroxy-2-methyl-propyl)-3-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl(3R)-10-(2-hydroxy-2-methyl-propyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(40.00 mg, 101.91 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (770.00mg, 6.75 mmol, 500.00 μL, 66.27 eq) with stirring at 25° C. for 1 h.LCMS indicated that thetert-butyl(3R)-10-(2-hydroxy-2-methyl-propyl)-3-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylatewas consumed completely and desired product was detected. The mixturewas directly evaporated in vacuo. The residue was not purified and usedin the next step. (45.00 mg, crude, TFA) was obtained as yellow oil andused in the next step.

Step 4. (3R)—N-(3-chloro-4-fluorophenyl)-10-(2-hydroxy-2-methylpropyl)-3-methyl-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(3R)-10-(2-hydroxy-2-methyl-propyl)-3-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(45.00 mg, 116.73 μmol, 1.00 eq, TFA) and TEA (67.23 mg, 664.38 μmol,92.10 μL, 6.00 eq) in DCM (5.00 mL) was added phenylN-(3-chloro-4-fluoro-phenyl)carbamate (32.36 mg, 121.80 μmol, 1.10 eq)with stirring at 25° C. for 16 h. LCMS indicated that the(3R)-10-(2-hydroxy-2-methyl-propyl)-3-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-onewas consumed completely and desired product was detected. The mixturewas directly evaporated in vacuo. The residue was purified by prep-HPLC(FA), following by by SFC (Instrument: SFC 80; Column: OD-10 um. Mobilephase: A for CO₂ and B for MeOH (0.1% NH₃H₂O); Gradient: B 30%; Flowrate: 60 mL/min; Back pressure: 100 bar; Column temperature: 35° C.;Wavelength: 220 nm.). The title compound (19.00 mg, 40.54 μmol, 36.62%yield, 99% purity) was obtained as white solid. LCMS: 464[M+1]. ¹H NMR(400 MHz, CDCl₃) δ=7.60 (dd, J=2.63, 6.54 Hz, 1H), 7.18-7.25 (m, 1H),7.00-7.09 (m, 1H), 6.61 (s, 1H), 5.14 (quin, J=6.57 Hz, 1H), 4.79-4.81(d, J=15.53 Hz, 1H), 4.37-4.48 (m, 3H), 3.55-3.69 (m, 4H), 3.00-3.03 (m,1H), 2.64-2.67 (d, J=15.89 Hz, 1H), 2.32-2.48 (m, 2H), 1.32 (s, 6H),1.18 (d, J=6.85 Hz, 3H).

Compound 049: (3R)—N-(3-chloro-4-fluorophenyl)-10-(2-hydroxyethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl(3R)-10-(2-hydroxyethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl(3R)-10-(2-methoxy-2-oxo-ethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Compound 048, product from Step 1, 50.00 mg, 127.40 μmol, 1.00 eq) inTH (5.00 mL) was added LiAlH₄ (9.67 mg, 254.80 μmol, 2.00 eq) at −78° C.with stirring under N₂. The mixture was warmed to 0° C. with stirringfor 2 h. TLC (PE: EtOAc=1:3) showed that the tert-butyl(3R)-10-(2-methoxy-2-oxo-ethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylateconsumed completely and one main new spot formed. LCMS indicated desiredproduct was detected. The mixture was quenched with 20 mL of water andextracted with EtOAc (20 mL*3). The organic phase was washed with brine(20 mL*1), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by prep-TLC (PE: EtOAc=1:3). The titlecompound (35.00 mg, 96.04 μmol, 75.38% yield) was obtained aslight-yellow oil.

Step 2.(3R)-10-(2-hydroxyethyl)-3-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl(3R)-10-(2-hydroxyethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(35.00 mg, 96.04 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (770.00mg, 6.75 mmol, 500.00 μL, 70.32 eq) at 20° C. with stirring for 1 h. TLC(PE: EtOAc=1:1) showed that the tert-butyl(3R)-10-(2-hydroxyethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylateconsumed completely and one new spot formed. The mixture wasconcentrated in vacuo to afford the title compound (40.00 mg, crude,TFA) as yellow oil and directly used in the next step.

Step 3. (3R)—N-(3-chloro-4-fluorophenvl)-10-(2-hydroxyethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(3R)-10-(2-hydroxyethyl)-3-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (40.00 mg, 105.72 μmol, 1.00eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (30.90 mg,116.29 mol, 1.10 eq) in DCM (3.00 mL) was added TEA (32.09 mg, 317.17μmol, 43.96 μL, 3.00 eq) with stirring at 20° C. for 16 h. LCMSindicated that reactant was consumed completely and 55% of desiredproduct. The mixture was concentrated invacuo, and the residue waspurified by prep-HPLC (FA). The title compound (17.50 mg, 38.14 μmol,36.08% yield, 95% purity) was obtained as white solid. LCMS: 436[M+1].¹H NMR (400 MHz, CDCl₃) δ=7.60 (dd, J=2.63, 6.54 Hz, 1H), 7.18-7.25 (m,1H), 7.00-7.09 (m, 1H), 6.61 (s, 1H), 5.12-5.15 (m, 1H), 4.09-4.85 (m,1H), 4.37-4.48 (m, 3H), 3.89-3.92 (m, 2H), 3.76-3.78 (m, 2H), 3.54-3.56(m, 2H), 3.00-3.04 (m, 1H), 2.65-2.69 (m, 1H), 2.34-2.37 (m, 2H), 1.17(d, J=6.85 Hz, 3H).

Compound 050:N-(3-chloro-4-fluorophenvl)-10-methyl-8-(methylamino)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.tert-buty110-methyl-8-(methylamino)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3] pyrazolo[2,4-b][1,4]diazepine-2-carboxylate. A mixture oftert-butyl10-methyl-8,11-dioxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxylate(Intermediate 2, 300.00 mg, 897.21 μmol, 1.00 eq), methylamine (7.5 M,239.26 μL, 2.00 eq, EtOH solution), CH₃COOH (53.88 mg, 897.21 μmol,51.31 μL, 1.00 eq) and 4A molecular sieve (400.00 mg) in DCE (8.00 mL)was stirred at 20° C. for 16 h. NaBH₃CN (281.90 mg, 4.49 mmol, 5.00 eq)was added and the mixture was stirred at 20° C. for 3 h. The mixture wasdiluted with EtOAc (40 mL) and washed with brine (40 mL). The organicphase was dried over Na₂SO₄, filtered and concentrated in vacuo, whichwas purified by silica gel column to afford the title compound (120.00mg, 309.07 μmol, 34.45% yield, 90% purity) as yellow oil.

LCMS: 350 [M+1].

Step 2. tert-butyl8-[allyloxycarbonyl(methyl)amino]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl10-methyl-8-(methylamino)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(116.00 mg, 314.80 μmol, 1.00 eq) and NaHCO₃ (79.34 mg, 944.40 μmol,36.73 μL, 3.00 eq) in THF (4.00 mL) and H₂O (1.00 mL) was added allylcarbonochloridate (49.33 mg, 409.24 mol, 43.27 μL, 1.30 eq), and themixture was stirred at 20° C. for 16 h. The mixture was diluted withEtOAc (40 mL) and washed with HCl (1 M, 40 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo, which waspurified by prep-TLC to afford the title compound (99.00 mg, 228.37μmol, 72.55% yield) as yellow oil.

Step 3. allylN-methyl-N-(10-methyl-11-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl)carbamate.To a solution of tert-butyl8-[allyloxycarbonyl(methyl)amino]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(108.00 mg, 249.13 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08g, 27.01 mmol, 2.00 mL, 108.43 eq) and the mixture was stirred at 25° C.under N₂ for 1 h. The mixture was concentrated in vacuo to afford thetitle compound (111.00 mg, 248.09 μmol, 99.58% yield, TFA) as yellowoil, which was used directly for the next step.

Step 4. allylN-[2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]-N-methyl-carbamate.A mixture of allylN-methyl-N-(10-methyl-11-oxo-2,3,4,7,8,9-hexahydro-11-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl)carbamate (111.00 mg, 248.09μmol, 1.00 eq, TFA), Et₃N (125.52 mg, 1.24 mmol, 171.95 μL, 5.00 eq) andphenyl N-(3-chloro-4-fluoro-phenyl)carbamate (72.50 mg, 272.90 μmol,1.10 eq) in DCM (5.00 mL) was stirred at 25° C. for 16 h. The mixturewas diluted with DCM (30 mL) and washed with HCl (1 M, 30 mL*2). Theorganic phase was dried over Na₂SO₄, filtered and concentrated in vacuo,which was purified by prep-TLC to afford (108.00 mg, 213.89 μmol, 86.21%yield) as yellow solid.

LCMS: 505/507 [M+1].

Step 5.N-(3-chloro-4-fluorophenyl)-10-methyl-8-(methylamino)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.A mixture of allylN-[2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]-N-methyl-carbamate(98.00 mg, 194.08 μmol, 1.00 eq),1,3-dimethylhexahydropyrimidine-2,4,6-trione (151.52 mg, 970.41 μmol,5.00 eq) and Pd(PPh₃)₄ (22.43 mg, 19.41 μmol, 0.10 eq) in THE (3.00 mL)was stirred at 25° C. for 16 h. The mixture was diluted with EtOAc (30mL) and washed with brine (30 mL). The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo, which was purified by silicagel column and prep-HPLC(HCl) to afford the title compound (55.00 mg,119.06 μmol, 61.35% yield, 99% purity, HCl) as yellow solid. ¹H NMR (400MHz, METHANOL-d₄) δ 7.60 (dd, J=2.57, 6.72 Hz, 1H), 7.24-7.37 (m, 1H),7.15 (t, J=8.99 Hz, 1H), 4.76-4.88 (m, 2H), 4.55 (s, 2H), 4.25-4.36 (m,1H), 3.86-3.97 (m, 1H), 3.71-3.82 (m, 1H), 3.23 (s, 5H), 2.83-2.89 (m,1H), 2.82-2.83 (m, 1H), 2.77 (s, 3H). LCMS: 421/423 [M+1].

Compound 051:N-(3-chloro-4-fluorophenvl)-8-(hydroxymethyl)-11-oxo-10-(2,2,2-trifluoroethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][,4]diazepine-2-carboxamide

Step 1. 5-tert-butyl 3-ethyl 2-[2-[(2,2,2-trifluoroethylamino)methyl]allyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate.A solution of 5-tert-butyl 3-ethyl2-[2-(chloromethyl)allyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate(500.00 mg, 1.30 mmol, 1.00 eq) and 2,2,2-trifluoroethanamine (3.86 g,39.00 mmol, 3.06 mL, 30.00 eq) in EtOH (50.00 mL) was stirred at 90° C.for 32 h. The mixture was diluted with EtOAc (120 mL) and washed withsaturated NaHCO₃ solution (120 mL). The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo which was purified by silicagel column to afford the title compound (460.00 mg, 1.03 mmol, 79.26%yield) as yellow oil.

LCMS: 447 [M+1].

Step 2. tert-butyl8-methylene-11-oxo-10-(2,2,2-trifluoroethyl)-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of 5-tert-butyl 3-ethyl2-[2-[(2,2,2-trifluoroethylamino)methyl]allyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate(460.00 mg, 1.03 mmol, 1.00 eq) in toluene (10.00 mL) was added Al(CH₃)₃(2 M, 2.06 mL, 4.00 eq) at −30° C. and the mixture was stirred at 60° C.for 16 h. The mixture was quenched with H₂O (10.00 mL). Na₂CO₃ (109.20mg, 1.03 mmol, 1.00 eq) and Boc₂O (269.84 mg, 1.24 mmol, 284.04 μL, 1.20eq) was added and the mixture was stirred at 20° C. for 16 h. Themixture was diluted with EtOAc (50 mL) and washed with HCl (1M, 50 mL).The organic phase was dried over Na₂SO₄, filtered and concentrated invacuo, which was purified by silica gel column to afford the titlecompound (390.00 mg, 974.05 μmol, 94.57% yield) as yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 5.07 (br d, J=4.16 Hz, 2H), 4.91 (s, 2H), 4.48-4.59(m, 2H), 4.08-4.20 (m, 2H), 3.97-4.05 (m, 2H), 3.56-3.73 (m, 2H),2.59-2.75 (m, 2H), 1.44-1.50 (m, 5H), 1.41 (s, 9H)._LCMS: 401 [M+1].

Step 3. tert-butyl8-(hydroxymethyl)-11-oxo-10-(2,2,2-trifluoroethyl)-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl8-methylene-11-oxo-10-(2,2,2-trifluoroethyl)-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(150.00 mg, 374.63 μmol, 1.00 eq) in THF (3.00 mL) was added BH₃.DMS (10M, 149.85 μL, 4.00 eq) at 0° C. and the mixture was stirred at 20° C.for 16 h. TLC indicated the starting material was consumed completely.H₂O₂ (297.30 mg, 2.62 mmol, 251.95 μL, 30% purity, 7.00 eq) and asolution of NaOH (74.93 mg, 1.87 mmol, 5.00 eq) in H₂O (500.00 uL) wasadded at −30° C., and the mixture was stirred at 20° C. for 2 h. Themixture was diluted with EtOAc (40 mL) and washed with saturated Na₂SO₃(30 mL), brine (30 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo, which was purified by prep-TLC toafford the title compound (86.00 mg, 199.37 μmol, 53.22% yield, 97%purity) as yellow oil.

LCMS: 419 [M+1].

Step 4.8-(hydroxymethyl)-10-(2,2,2-trifluoroethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl8-(hydroxymethyl)-11-oxo-10-(2,2,2-trifluoroethyl)-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(106.00 mg, 253.34 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08g, 27.01 mmol, 2.00 mL, 106.63 eq) and the mixture was stirred at 25° C.under N₂ for 1 h. The mixture was concentrated in vacuo to afford thetitle compound (109.00 mg, 252.13 μmol, 99.52% yield, TFA) as yellowoil, which was used directly for the next step.

Step 5.N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-11-oxo-10-(2,2,2-trifluoroethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of8-(hydroxymethyl)-10-(2,2,2-trifluoroethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(109.00 mg, 252.13 μmol, 1.00 eq, TFA), Et₃N (127.56 mg, 1.26 mmol,174.74 μL, 5.00 eq) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate(73.68 mg, 277.34 μmol, 1.10 eq) in DCM (5.00 mL) was stirred at 25° C.for 16 h. The mixture was diluted with DCM (30 mL) and washed with HCl(1 M, 30 mL). The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo, which was purified by prep-HPLC(FA) to afford thetitle compound (56.00 mg, 113.18 μmol, 44.89% yield, 99% purity) asyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (dd, J=2.63, 6.54 Hz, 1H),7.17-7.24 (m, 1H), 7.03-7.12 (m, 1H), 6.56 (s, 1H), 4.76-4.92 (m, 1H),4.65-4.72 (m, 2H), 4.30-4.49 (m, 2H), 3.78-3.95 (m, 2H), 3.63-3.76 (m,3H), 3.46-3.61 (m, 2H), 2.82-2.92 (m, 2H), 2.71-2.81 (m, 1H). LCMS:490/492 [M+1].

Compound 052: Ethyl2-((3-chloro-4-fluorophenyl)carbamoyl)-8,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate

Step 1. 2-tert-butyl 8-ethyl8,10-dimethyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate.To a solution of 2-tert-butyl 8-ethyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate(Intermediate 14, 200.00 mg, 509.62 μmol, 1.00 eq) in THF (6.00 mL) wasadded LDA (1 M, 1.53 mL, 3.00 eq) at −65° C. under N₂, followed by Me(217.01 mg, 1.53 mmol, 95.18 μL, 3.00 eq) after 0.5 h and the mixturewas stirred at 25° C. for 2 h. The mixture was quenched with HCl (1M, 40mL) and extracted with EtOAc (40 mL). The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byprep-TLC to afford the title compound (140.00 mg, 309.99 μmol, 60.83%yield, 90% purity) as yellow oil.

LCMS: 407 [M+1].

Step 2. ethyl 8,10-dimethyl-11-oxo-1,2,3,4,7,9-hexahydropyrido [2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate. To a solution of2-tert-butyl 8-ethyl8,10-dimethyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate(210.00 mg, 516.63 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (4.62g, 40.52 mmol, 3.00 mL, 78.43 eq) and the mixture was stirred at 25° C.under N₂ for 1 h. The mixture was concentrated in vacuo to afford thetitle compound (217.00 mg, 516.20 μmol, 99.92% yield, TFA) as yellowoil, which was used directly for the next step.

Step 3. ethyl2-((3-chloro-4-fluorophenyl)carbamoyl)-8,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate. A mixture of ethyl8,10-dimethyl-11-oxo-1,2,3,4,7,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate (217.00 mg, 516.20 μmol, 1.00 eq,TFA), Et₃N (261.17 mg, 2.58 mmol, 357.77 μL, 5.00 eq) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (150.85 mg, 567.82 μmol, 1.10 eq)in DCM (7.00 mL) was stirred at 25° C. for 16 h. The mixture was dilutedwith DCM (30 mL) and washed with HCl (1 M, 30 mL). The organic phase wasdried over Na₂SO₄, filtered and concentrated in vacuo, which waspurified by prep-HPLC(FA) to afford the title compound (175.00 mg,362.51 mol, 70.23% yield, 99% purity) as white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, J=2.69, 6.48 Hz, 1H), 7.15-7.23 (m,1H), 7.01-7.09 (m, 1H), 6.63 (s, 1H), 4.70 (s, 1H), 4.54-4.65 (m, 2H),4.21-4.32 (m, 3H), 3.79-3.91 (m, 2H), 3.70-3.78 (m, 1H), 3.22 (d,J=15.04 Hz, 1H), 3.17 (s, 3H), 2.79-2.88 (m, 2H), 1.31-1.36 (m, 6H).LCMS: 478/480 [M+1].

Compound 053:N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-8,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

To a solution of ethyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-8,10-dimethyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate(Compound 052, 60.00 mg, 125.54 μmol, 1.00 eq) in THF (5.00 mL) wasadded LiBH₄ (8.20 mg, 376.62 μmol, 3.00 eq) at 0° C. and the mixture wasstirred at 25° C. for 2 h. The mixture was quenched with H₂O (30 mL) andextracted with EtOAc (30 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified byprep-HPLC(FA) to afford the title compound (34.00 mg, 77.22 μmol, 61.51%yield, 99% purity) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (dd,J=2.63, 6.54 Hz, 1H), 7.20 (br d, J=1.34 Hz, 1H), 7.07 (s, 1H), 6.62 (s,1H), 4.64-4.74 (m, 2H), 4.19 (s, 1H), 4.01 (s, 1H), 3.87 (s, 1H),3.50-3.66 (m, 2H), 3.37 (d, J=14.79 Hz, 1H), 3.22 (s, 3H), 3.03-3.11 (m,1H), 2.85 (s, 1H), 1.88-1.97 (m, 1H), 1.16 (s, 3H). LCMS: 436/438 [M+1].

Compound 054:N-(3-chloro-4-fluorophenyl)-8-(3,3-difluoropyrrolidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-(3,3-difluoropyrrolidin-1-yl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of 3,3-difluoropyrrolidine (96.09 mg, 669.34 μmol, 1.49eq, HCl) in DCE (4.00 mL) was added NaOAc (73.60 mg, 897.20 μmol, 2.00eq). After stirring for 1 hr, tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (150.00 mg, 448.60 μmol, 1.00 eq)and 4A MS (300.00 mg) was added. The mixture was stirred at 20° C. for 4hr. NaBH₃CN (112.76 mg, 1.79 mmol, 4.00 eq) was added. Then the mixturewas stirred at 20° C. for 12 hr. LCMS showed the reaction completed. Themixture was poured into saturated NH₄Cl (20 mL), extracted with DCM (10mL*2). The organic layer was washed with brine (20 mL*2), dried overanhydrous Na₂SO₄ and concentrated in vacuum to give the crude, which waspurified by prep.TLC (100% Ethyl acetate) to afford the title compound(120.00 mg, 282.04 μmol, 62.87% yield) as colorless oil.

LCMS: 426 [M+1].

Step 2.8-(3,3-difluoropyrrolidin-1-yl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution tert-butyl8-(3,3-difluoropyrrolidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(90.00 mg, 211.53 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g,27.01 mmol, 2.00 mL, 127.70 eq). The mixture was stirred at 20° C. for 1hr. TLC showed the reaction completed. The mixture was concentrated toafford the title compound (90.00 mg, 204.83 μmol, 96.83% yield, TFA) asthe colorless oil, which was used directly.

Step 3.N-(3-chloro-4-fluorophenvl)-8-(3,3-difluoropyrrolidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of8-(3,3-difluoropyrrolidin-1-yl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(90.00 mg, 204.83 μmol, 1.00 eq, TFA) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (55.52 mg, 209.00 μmol, 1.00 eq)in DCM (2.00 mL) was added TEA (62.18 mg, 614.50 μmol, 85.18 μL, 3.00eq). The mixture was stirred at 20° C. for 12 h. LCMS showed thereaction was completed. The mixture was concentrated in vacuum to givethe crude, which was purified by prep-HPLC to afford the title compound(57.00 mg, 113.56 μmol, 55.44% yield, 99% purity) as white solid. LCMS:497/499 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, J=2.57, 6.48 Hz, 1H),7.15-7.22 (m, 1H), 6.99-7.09 (m, 1H), 6.58 (s, 1H), 4.67 (s, 2H),4.31-4.46 (m, 2H), 3.79-3.98 (m, 2H), 3.44 (d, J=5.38 Hz, 2H), 3.29-3.31(m, 1H), 3.20 (s, 3H), 2.81-3.12 (m, 6H), 2.28-2.33 (m, 2H).

Compound 055:N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-8-(piperidin-1-yl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl10-methyl-11-oxo-8-(1-piperidyl)-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido [2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (120.00 mg, 358.88 μmol,1.00 eq) and piperidine (61.12 mg, 717.76 μmol, 71.07 μL, 2.00 eq) inDCE (2.00 mL) was added HOAc (21.55 mg, 358.88 μmol, 20.52 μL, 1.00 eq),4A MS (300.00 mg), the mixture was stirred at 20° C. for 3 hr. NaBH₃CN(112.76 mg, 1.79 mmol, 5.00 eq) was added and the mixture was stirred at20° C. for 12 hr. TLC showed the reaction was completed. The mixture waspoured into saturated NH₄Cl (20 mL), extracted with Ethyl acetate (15mL*2). The organic layer was washed with brine (20 mL*2), dried overanhydrous Na₂SO₄ and concentrated in vacuum. The crude was purified byprep. TLC to afford the title compound (50.00 mg, 111.52 mol, 31.07%yield, 90% purity) as colorless oil.

Step 2.10-methyl-8-(1-piperidyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl10-methyl-1-oxo-8-(1-piperidyl)-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(50.00 mg, 123.91 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (14.13mg, 123.91 μmol, 9.17 μL, 1.00 eq). The mixture was stirred at 20° C.for 1 hr. TLC showed the reaction was completed. The mixture wasconcentrated in vacuum to afford the title compound (50.00 mg, 119.78mol, 96.67% yield, TFA) as colorless oil, which was used for the nextstep without purification.

Step 3.N-(3-chloro-4-fluorophenvl)-10-methyl-1-oxo-8-(piperidin-1-yl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. To a solution of10-methyl-8-(1-piperidyl)-2,3,4,7,8,9-hexahydro-1H-pyrido [2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (50.00 mg, 119.78 μmol, 1.00 eq,TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (31.82 mg, 119.78μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (36.36 mg, 359.35 μmol,49.81 μL, 3.00 eq). The mixture was stirred at 20° C. for 16 hr. LCMSshowed the reaction was completed. The mixture was concentrated invacuum to give the crude. The crude was purified by prep-HPLC to affordthe title compound (22.00 mg, 45.86 μmol, 38.28% yield, 99% purity) aswhite solid. LCMS: 475/477 [M+]¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H),7.58 (dd, J=2.63, 6.54 Hz, 1H), 7.17-7.24 (m, 1H), 7.05 (t, J=8.80 Hz,1H), 6.73 (s, 1H), 4.67-4.76 (m, 2H), 4.58-4.67 (m, 1H), 4.35 (dd,J=6.54, 15.34 Hz, 1H), 3.87-3.95 (m, 1H), 3.67-3.82 (m, 3H), 3.54-3.59(m, 1H), 3.18 (s, 3H), 2.79-2.93 (m, 4H), 2.65-2.78 (m, 2H), 1.66-1.80(m, 4H), 1.47-1.64 (m, 2H).

Compound 056:N-(3-chloro-4-fluorophenyl)-8-(4,4-difluoropiperidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-(4,4-difluoro-1-piperidyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate. To a solution of tert-butyl10-methyl-8,11-dioxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (150.00 mg, 448.60 μmol,1.00 eq) and 4,4-difluoropiperidine (108.68 mg, 897.22 μmol, 2.00 eq) inDCE (2.00 mL) was added 4A MS (300.00 mg) and HOAc (26.94 mg, 448.60μmol, 25.66 μL, 1.00 eq), the mixture was stirred at 20° C. for 16 hr.NaBH₃CN (140.95 mg, 2.24 mmol, 5.00 eq) was added. The mixture wasstirred at 20° C. for 3 hr. TLC showed the reaction was completed. Themixture was poured into saturated NH₄Cl (20 mL), extracted with Ethylacetate (15 mL*2), the organic layer was washed with brine (20 mL*2),dried over anhydrous Na₂SO₄ and concentrated in vacuum. The crude waspurified by prep-TLC to afford the title compound (53.00 mg, 114.56μmol, 25.54% yield, 95% purity) as colorless oil.

Step 2.8-(4,4-difluoro-1-piperidyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl8-(4,4-difluoro-1-piperidyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(53.00 mg, 120.59 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g,27.01 mmol, 2.00 mL, 224.01 eq), the mixture was stirred at 20° C. for 1hr. TLC showed the reaction complete. The mixture was concentrated invacuum to afford the title compound (54.00 mg, 119.10 μmol, 98.76%yield, TFA) as colorless oil, which was used for the next step withoutpurification.

Step 3.N-(3-chloro-4-fluorophenyl)-8-(4,4-difluoropiperidin-1-yl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of8-(4,4-difluoro-1-piperidyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(54.00 mg, 119.10 μmol, 1.00 eq, TFA) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (31.64 mg, 119.10 μmol, 1.00 eq)in DCM (2.00 mL) was added TEA (36.15 mg, 357.29 μmol, 49.53 μL, 3.00eq). The mixture was stirred at 20° C. for 16 hr. LCMS showed thereaction complete. The mixture was concentrated in vacuum. The crude waspurified by prep-HPLC to afford the title compound (24.00 mg, 45.09μmol, 37.86% yield, 96% purity) as white solid. LCMS: 511/513 [M+1]. ¹HNMR (400 MHz, CDCl₃) δ 7.58 (dd, J=2.64, 6.53 Hz, 1H), 7.18-7.20 (m,1H), 7.02-7.08 (m, 1H), 6.65 (s, 1H), 4.51-4.80 (m, 3H), 4.28-4.39 (m,1H), 3.76-3.93 (m, 2H), 3.47-3.63 (m, 2H), 3.28-3.40 (m, 1H), 3.18 (s,3H), 2.74-2.89 (m, 4H), 2.63-2.67 (m, 2H), 1.92-2.10 (m, 4H).

Compound 057: methyl2-((3-chloro-4-fluorophenvl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylate

Step 1. 2-tert-butyl 9-methyl10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylateand 2-tert-butyl 9-methyl9,10-dimethyl-11-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylate.To a solution of 2-tert-butyl 9-methyl11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylate (Intermediate 13,1.10 g, 3.02 mmol, 1.00 eq) in DMF (20.00 mL) was added NaH (144.90 mg,3.62 mmol, 60% purity, 1.20 eq) at −30° C., stirring for 30 min Mel(557.01 mg, 3.93 mmol, 244.30 μL, 1.30 eq) was added and the mixture wasstirred at 20° C. for 2 hr. LCMS showed the reactant consumed and 70% of2-tert-butyl 9-methyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylateand 18% of 2-tert-butyl 9-methyl9,10-dimethyl-11-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylatewere detected. The mixture was poured into water (100 mL), extractedwith ethyl acetate (50 mL*3), the organic layer was washed with brine(50 mL*3), dried over anhydrous Na₂SO₄ and concentrated in vacuum. Thecrude was purified by prep-HPLC to afford 2-tert-butyl 9-methyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylate(680.00 mg, 1.80 mmol, 59.60% yield) and 2-tert-butyl 9-methyl9,10-dimethyl-11-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylate(120.00 mg, 305.77 μmol, 10.12% yield) as colorless oil.

Step 2.methyl-10-methyl-11-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylate.To a solution of 2-tert-butyl 9-methyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylate(200.00 mg, 528.51 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (4.62g, 40.52 mmol, 3.00 mL, 76.67 eq). The mixture was stirred at 20° C. for1 hr. TLC (Petroleum ether: ethyl acetate=1:1) showed the reaction wascompleted. The mixture was concentrated in vacuum to afford the titlecompound (200.00 mg, 509.77 μmol, 96.46% yield, TFA) as colorless oil.

Step 3. methyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylate.To a solution of methyl 10-methyl-11-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3] pyrazolo[2,4-c][1,4]diazepine-9-carboxylate (190.00 mg, 484.29μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate(128.66 mg, 484.29 μmol, 1.00 eq) in DCM (3.00 mL) was added TEA (98.01mg, 968.57 μmol, 134.26 μL, 2.00 eq). The mixture was stirred at 20° C.for 16 hr. LCMS showed the reaction was completed. The mixture waspoured into water (20 mL), extracted with ethyl acetate (20 mL*2), theorganic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄and concentrated in vacuum. The crude was purified by prep-HPLC toafford the title compound (150.00 mg, 323.43 μmol, 66.79% yield, 97%purity) as white solid.

LCMS: 450/452 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (dd, J=2.63, 6.54Hz, 1H), 7.18-7.24 (m, 1H), 7.00-7.09 (m, 1H), 6.64 (s, 1H), 4.59-4.80(m, 2H), 4.28-4.47 (m, 3H), 3.74-3.95 (m, 2H), 3.67 (s, 3H), 3.20 (s,3H), 2.88-2.99 (m, 1H), 2.81 (t, J=5.81 Hz, 2H), 2.49-2.65 (m, 1H).

Compound 058:2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylicAcid

To a solution of methyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylate(Compound 057, 30.00 mg, 66.69 μmol, 1.00 eq) in MeOH (2.00 mL) and H₂O(2.00 mL) was added NaOH (8.00 mg, 200.07 μmol, 3.00 eq), the mixturewas stirred at 20° C. for 16 hr. LCMS showed the reaction was completed.The mixture was acidified by HCl (1N) to pH 4. The residue was purifiedby prep-HPLC to afford the title compound (24.00 mg, 54.52 μmol, 81.74%yield, 99% purity) as white solid LCMS: 436/438 [M+1] ¹H NMR (400 MHz,METHANOL-d₄) δ 7.56-7.64 (m, 1H), 7.25-7.35 (m, 1H), 7.13 (t, J=8.93 Hz,1H), 4.60 (br s, 2H), 4.37 (br d, J=5.01 Hz, 3H), 3.84-3.99 (m, 1H),3.59-3.75 (m, 1H), 3.17 (s, 3H), 2.93 (br d, J=14.43 Hz, 1H), 2.75 (brt, J=5.32 Hz, 2H), 2.53 (br dd, J=5.93, 14.61 Hz, 1H).

Compound 059:N2-(3-chloro-4-fluorophenyl)-N9,N9,10-trimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,9-dicarboxamide

To a solution of2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylicacid (Compound 058, 100.00 mg, 229.44 μmol, 1.00 eq) and Me₂NH (187.09mg, 2.29 mmol, 210.21 μL, 10.00 eq, HCl) in DMF (3.00 mL) was addedDIPEA (593.06 mg, 4.59 mmol, 801.43 μL, 20.00 eq) and HATU (104.69 mg,275.33 mol, 1.20 eq). The mixture was stirred at 20° C. for 16 hr. LCMSshowed the reaction was completed. The mixture was poured into water (20mL), extracted with ethyl acetate (20 mL*2), the organic layer waswashed with brine (20 mL*3), dried over anhydrous Na₂SO₄ andconcentrated in vacuum. The residue was purified by prep-HPLC to affordthe title compound (50.00 mg, 106.93 μmol, 46.61% yield, 99% purity) aswhite solid. LCMS: 463/465 [M+1]. ¹H NMR (400 MHz, CDCl₃) (7.60 (dd,J=2.63, 6.54 Hz, 1H), 7.18-7.25 (m, 1H), 7.04 (t, J=8.80 Hz, 1H), 6.77(s, 1H), 4.75 (q, J=15.89 Hz, 2H), 4.61 (dd, J=4.52, 7.58 Hz, 1H), 4.51(td, J=4.52, 14.31 Hz, 1H), 4.18 (ddd, J=4.71, 10.33, 14.55 Hz, 1H),3.76-3.94 (m, 2H), 3.07 (s, 3H), 3.03 (d, J=8.31 Hz, 6H), 2.75-2.84 (m,2H), 2.50-2.64 (m, 2H).

Compound 060:N-(3-chloro-4-fluorophenvl)-9-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

To a solution of methyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylate(Compound 057, 100.00 mg, 222.29 μmol, 1.00 eq) in THF (3.00 mL) wasadded LiBH₄ (14.52 mg, 666.87 μmol, 3.00 eq) at 10° C. The mixture wasstirred at 20° C. for 16 hr. LCMS showed the reaction was completed. Themixture was poured into aqueous HCl (0.5 M), extracted with DCM (20mL*2), the organic layer was washed with brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuum. The crude was purified byprep-HPLC to afford the title compound (43.00 mg, 100.91 μmol, 45.40%yield, 99% purity) as white solid. LCMS: 422/424 [M+1]. ¹H NMR (400 MHz,CDCl₃) δ 7.57 (dd, J=2.63, 6.54 Hz, 1H), 7.18-7.25 (m, 1H), 7.04 (t,J=8.80 Hz, 1H), 6.90 (s, 1H), 4.66 (s, 2H), 4.32-4.52 (m, 2H), 3.90 (td,J=5.61, 13.36 Hz, 1H), 3.69-3.83 (m, 4H), 3.21 (s, 3H), 2.80 (t, J=5.75Hz, 2H), 2.21-2.57 (m, 3H).

Compound 061:N-(3-chloro-4-fluorophenvl)-9-(hydroxymethyl)-9,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. 2-tert-butyl 9-methyl9,10-dimethyl-11-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylate.To a solution of methyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-9,10-dimethyl-11-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylate(100.00 mg, 285.41 μmol, 1.00 eq) in DMF (3.00 mL) was added NaH (34.25mg, 856.23 μmol, 60% purity, 3.00 eq), stirring for 30 min, Mel (202.56mg, 1.43 mmol, 88.84 μL, 5.00 eq) was added and the mixture was stirredat 20° C. for 2 hr. LCMS showed the reactant consumed and the majorproduct was detected. The mixture was poured into water (10 mL),extracted with ethyl acetate (10 mL*2). The combined organic layer waswashed with brine (10 mL*2), dried over anhydrous Na₂SO₄ andconcentrated in vacuum to afford the title compound (120.00 mg, crude)as the yellow oil.

Step 2. methyl9,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylate. To a solution of2-tert-butyl 9-methyl9,10-dimethyl-11-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,9-dicarboxylate(120.00 mg, 305.77 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (4.62g, 40.52 mmol, 3.00 mL, 132.52 eq). The mixture was stirred at 20° C.for 1 hr. TLC showed the reaction was completed. The mixture wasconcentrated in vacuum to givemethyl9,10-dimethyl-11-oxo-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4] diazepine-9-carboxylate (120.00 mg, 295.30 μmol, 96.58%yield, TFA) as the colorless oil, which was used for the next stepwithout purification.

Step 3. methyl2-((3-chloro-4-fluorophenvl)carbamoyl)-9,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylate. To a solution of methyl9,10-dimethyl-11-oxo-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylate (120.00 mg, 295.30 μmol,1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (78.45mg, 295.30 μmol, 1.00 eq) in DCM (3.00 mL) was added TEA (365.00 mg,3.61 mmol, 500.00 μL, 12.21 eq). The mixture was stirred at 20° C. for16 hr. TLC showed the reaction was completed. The reaction mixture waspartitioned between ethyl acetate (20 mL) and water (20 mL) andextracted with ethyl acetate (20 mL*2), the organic layer was washedwith brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated invacuum. The crude was purified by prep-TLC to afford the title compound(90.00 mg, 188.19 μmol, 63.73% yield, 97% purity) as white solid.

Step 4.N-(3-chloro-4-fluorophenyl)-9-(hydroxymethyl)-9,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of methyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-9,10-dimethyl-11-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylate(45.00 mg, 97.01 mol, 1.00 eq) in THF (2.00 mL) was added LiBH₄ (4.23mg, 194.02 μmol, 2.00 eq) at 0° C. The mixture was stirred at 20° C. for16 hr. LCMS showed 15% reactant remained and LiBH₄ (4.23 mg, 194.02μmol, 2.00 eq) was added, the mixture was stirred at 20° C. for 4 hr.LCMS showed the reaction was completed. The mixture was poured intoaqeuous HCl (0.5M), extracted with DCM (20 mL*2), the organic layer waswashed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentratedin vacuum. The crude was purified by prep-HPLC to afford the titlecompound (22.00 mg, 49.46 μmol, 50.99% yield, 98% purity) as whitesolid. LCMS: 436/438 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (dd, J=2.64,6.53 Hz, 1H), 7.22 (ddd, J=2.76, 4.08, 8.97 Hz, 1H), 7.00-7.09 (m, 1H),6.79 (s, 1H), 4.64-4.75 (m, 2H), 4.51-4.59 (m, 1H), 4.38-4.47 (m, 1H),3.77-3.92 (m, 3H), 3.55 (d, J=11.29 Hz, 1H), 3.12 (s, 3H), 2.80 (t,J=5.77 Hz, 2H), 2.49-2.63 (m, 1H), 2.27 (ddd, J=2.38, 8.28, 15.56 Hz,2H), 1.44 (s, 3H).

Compound 062:2-((3-chloro-4-fluorophenvl)carbamoyl)-9,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylicacid

To a solution of methyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-9,10-dimethyl-11-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-9-carboxylate(10.00 mg, 21.56 μmol, 1.00 eq) in MeOH (1.00 mL) and H₂O (1.00 mL) wasadded NaOH (1.29 mg, 32.34 μmol, 1.50 eq). The mixture was stirred at20° C. for 16 hrs. LCMS showed 60% reactant remained, NaOH (2.59 mg,64.67 mol, 3.00 eq) was added. The mixture was heated to 40° C. andstirred at 40° C. for 16 hr. LCMS showed the reaction completed. Themixture was acidified to pH 3 by HCl (3 M). The resulting mixture waspurified by prep-HPLC to afford the title compound (7.00 mg, 15.09 μmol,70.01% yield, 97% purity) as white solid. LCMS: 450/452 [M+1]. ¹H NMR(400 MHz, CDCl₃) δ 7.45 (dd, J=2.51, 6.27 Hz, 1H), 7.11-7.20 (m, 1H),7.01-7.08 (m, 1H), 6.80 (br s, 1H), 6.74-6.86 (m, 1H), 4.70-4.75 (m,1H), 4.21-4.45 (m, 3H), 3.93 0.396 (m, 1H), 3.56 (br s, 1H), 3.17 (s,4H), 2.70-2.92 (m, 2H), 2.08-2.23 (m, 1H), 1.66 (s, 3H).

Compound 063:N-(3-chloro-4-fluorophenyl)-10-methyl-8-(morpholinomethyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of2-tert-butyl8-ethyl10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate (Intermediate 14,500.00 mg, 1.27 mmol, 1.00 eq) in THF (10.00 mL) was added LiAlH₄ (96.39mg, 2.54 mmol, 2.00 eq) at −40° C. under N₂, then the mixture wasstirred at −40° C. for 2 hr under N2 atmosphere. The mixture was pouredinto ice-water (20 mL) and stirred at 5 min. The aqueous phase wasextracted with ethyl acetate (10 mL*3). The combined organic phase waswashed with HCl (1N, 20 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 1:2) toafford the title compound (120.00 mg, 342.46 μmol, 26.97% yield) as awhite solid. LCMS: 351 [M+1].

Step 2.tert-butyl10-methyl-8-(methylsulfonyloxymethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture oftert-butyl8-(hydroxymethyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(100.00 mg, 285.38 μmol, 1.00 eq), TEA (144.39 mg, 1.43 mmol, 197.79 μL,5.00 eq) in DCM (3.00 mL) was added MsCl (130.76 mg, 1.14 mmol, 88.35μL, 4.00 eq) at 0° C. under N₂, and then the mixture was stirred at 15°C. for 2 hour under N2 atmosphere. LCMS and TLC showed the startingmaterial was consumed completely, a new spot appeared. The mixture waspoured into ice-water (20 mL) and stirred at 5 min. The aqueous phasewas extracted with DCM (10 mL*2). The combined organic phase was washedwith brine (20 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum to afford the title compound (102.00 mg, 238.04μmol, 83.41% yield) as a white solid, which was used directly for nextstep. LCMS 429 [M+1].

Step 3.tert-butyl10-methyl-8-(morpholinomethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of tert-butyl10-methyl-8-(methylsulfonyloxymethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(100.00 mg, 233.37 μmol, 1.00 eq), morpholine (203.31 mg, 2.33 mmol,205.37 μL, 10.00 eq) in DMSO (2.00 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 88° C. for 16 hourunder N2 atmosphere. LCMS showed the starting material was consumedcompletely, desired product was major. The mixture was poured into water(10 mL) and extracted with EtOAc (5 mL*3). The combined organic phasewas washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by Prep-TLC(DCM/MeOH=20/1) to afford the title compound (65.00 mg, 147.19 μmol,63.07% yield, 95% purity) as a white solid.

LCMS: 420 [M+1].

Step 4. 10-methyl-8-(morpholinomethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one. A mixture oftert-butyl10-methyl-8-(morpholinomethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(65.00 mg, 154.94 μmol, 1.00 eq), TFA (1.54 g, 13.51 mmol, 1.00 mL,87.17 eq) in DCM (2.00 mL) was degassed and purged with N₂ for 3 times,and then the mixture was stirred at 20° C. for 1 hour under N2atmosphere. TLC showed the starting material was consumed completely, anew spot appeared. The mixture was concentrated in vacuum to afford thetitle compound (67.00 mg, 154.58 μmol, 99.77% yield, TFA) as a yellowoil, which was used directly for next step.

Step 5.N-(3-chloro-4-fluorophenvl)-10-methyl-8-(morpholinomethyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of10-methyl-8-(morpholinomethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (67.00 mg, 209.77 μmol, 1.00eq), phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (66.88 mg, 251.72μmol, 1.20 eq), TEA (42.45 mg, 419.54 μmol, 58.15 μL, 2.00 eq) in DCM(5.00 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 20° C. for 16 hour under N2 atmosphere. LCMSshowed the starting material was consumed completely, desired productwas major. The mixture was poured into water (10 mL) and stirred at 5min. The aqueous phase was extracted with DCM (5 mL*3). The combinedorganic phase was washed with brine (10 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byPrep-HPLC (FA) to afford the title compound (60.00 mg, 120.99 μmol,57.68% yield, 99% purity) as a white solid. LCMS: 491/493 [M+1]. ¹H NMR(400 MHz, CDCl₃) δ 7.58 (dd, J=2.63, 6.54 Hz, 1H), 7.18-7.24 (m, 1H),7.01-7.09 (m, 1H), 6.72 (s, 1H), 4.67 (s, 2H), 4.38-4.47 (m, 1H),4.11-4.20 (m, 1H), 3.74-3.92 (m, 6H), 3.49 (m, 1H), 3.28 (m, 1H), 3.17(s, 3H), 2.75-2.91 (m, 4H), 2.67 (m, 4H), 2.48-2.56 (m, 1H).

Compound 064:N-(3-chloro-4-fluorophenvl)-10-methyl-11-oxo-8-(piperidin-1-ylmethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of tert-butyl10-methyl-8-methylene-1-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 1, 800.00 mg, 2.41 mmol, 1.00 eq), chlororhodium;triphenylphosphane (89.19 mg, 96.40 μmol, 0.04 eq) in THF (10.00 mL) wasadded 1,3,2-benzodioxaborole (1 M, 7.23 mL, 3.00 eq) at 0° C. under N₂,and then the mixture was stirred at 20° C. for 3 hr under N2 atmosphere.TLC showed the starting material was consumed completely. A solution ofsodium; hydroxide (482.00 mg, 12.05 mmol, 5.00 eq) in H₂O (5.00 mL) wasadded at −30° C. dropwise, then hydrogen peroxide (1.91 g, 16.87 mmol,1.62 mL, 30% purity, 7.00 eq) was added slowly. The mixture was stirredat 20° C. for 16 hr. TLC showed no starting material, desired productwas major. The mixture was quenched with NaHSO₃ (saturated, 40 mL) andextracted with EtOAc (20 mL). The organic phase was washed with NaOH(15%, 40 mL*3) and brine, dried over Na₂SO₄, filtered and concentratedin vacuo to give brown oil. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/4) toafford the title compound (522.00 mg, 1.42 mmol, 58.72% yield, 95%purity) as a white solid.

LCMS: 351 [M+1].

Step 2.tert-butyl10-methyl-8-(methylsulfonyloxymethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of tert-butyl8-(hydroxymethyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(500.00 mg, 1.43 mmol, 1.00 eq), TEA (723.51 mg, 7.15 mmol, 991.11 μL,5.00 eq) in DCM (10.00 mL) was added MsCl (655.23 mg, 5.72 mmol, 442.72μL, 4.00 eq) at 0° C. under N₂, and then the mixture was stirred at 20°C. for 2 hour under N2 atmosphere. TLC showed the starting material wasconsumed completely, a new spot appeared. The mixture was poured intoice-water (20 mL) and stirred at 5 min. The aqueous phase was extractedwith DCM (10 mL*2). The combined organic phase was washed with brine (20mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum toafford the title compound (550.00 mg, 1.09 mmol, 76.29% yield, 85%purity) as a colorless oil.

LCMS: 429 [M+1].

Step 3.tert-butyl10-methyl-11-oxo-8-(1-pipenridylmethyl)-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of tert-butyl10-methyl-8-(methylsulfonyloxymethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(120.00 mg, 280.05 μmol, 1.00 eq), piperidine (238.46 mg, 2.80 mmol,277.28 μL, 10.00 eq) in DMSO (2.00 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 88° C. for 16 hourunder N2 atmosphere. LCMS showed the starting material was consumedcompletely, desired product was major. The mixture was poured into water(10 mL). The aqueous phase was extracted with ethyl acetate (5 mL*2).The combined organic phase was washed with brine (10 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by Prep-TLC (DCM/MeOH=10/1) to afford the title compound (60.00mg, 143.70 mol, 51.31% yield) as a white solid. LCMS: 418 [M+1]

Step 4.10-methyl-8-(1-piperidylmethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.A mixture of tert-butyl10-methyl-1-oxo-8-(1-piperidylmethyl)-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(54.00 mg, 129.33 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g,13.51 mmol, 1.00 mL, 104.43 eq), and then the mixture was stirred at 20°C. for 1 hour under N2 atmosphere. TLC showed the starting material wasconsumed completely, a new spot appeared. The mixture was concentratedin vacuum to afford the title compound (55.80 mg, 129.33 μmol, 100.00%yield, TFA) as a yellow oil, which was used directly for next step.

Step 5.N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-8-(piperidin-1-ylmethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.A mixture of10-methyl-8-(1-piperidylmethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(55.80 mg, 129.33 μmol, 1.00 eq, TFA), phenylN-(3-chloro-4-fluoro-phenyl)carbamate (41.23 mg, 155.20 mol, 1.20 eq),TEA (26.17 mg, 258.66 μmol, 35.85 μL, 2.00 eq) in DCM (5.00 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 20° C. for 16 hour under N2 atmosphere. LCMS showed thestarting material was consumed completely, desired product was major.The mixture was poured into water (10 mL) and stirred at 5 min. Theaqueous phase was extracted with DCM (5 mL*3). The combined organicphase was washed with brine (10 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byPrep-HPLC (HCl) to afford the title compound (40.00 mg, 80.98 μmol,62.62% yield, 99% purity) as a white solid. LCMS: 489/491 [M+1]. ¹H NMR(400 MHz, CDCl₃) δ 7.60 (m, 1H), 7.18 (m, 1H), 7.02-7.10 (m, 1H), 6.60(br s, 1H), 4.57-4.77 (m, 2H), 4.48 (m, 1H), 4.35 (m, 1H), 3.84 (m, 3H),3.68 (m, 1H), 3.32-3.58 (m, 3H), 3.24 (m, 3H), 2.63-3.08 (m, 6H), 2.37(m, 2H), 1.81-2.02 (m, 3H), 1.48 (m, 1H).

Compound 065:N-(3-chloro-4-fluorophenvl)-8-((dimethylamino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.tert-butyl8-[(dimethylamino)methyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate. A mixture oftert-butyl10-methyl-8-(methylsulfonyloxymethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Compound 064, product from Step 2, 120.00 mg, 280.05 μmol, 1.00 eq),N-methylmethanamine (2 M, 1.40 mL, 10.00 eq) in DMSO (5.00 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 88° C. for 16 hour under N2 atmosphere. TLC showed thestarting material was consumed completely, desired product was major.The mixture was poured into water (10 mL) and extracted with EtOAc (5mL*3). The combined organic phase was washed with brine (10 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by Prep-TLC (DCM/MeOH=10/1) to afford the title compound(65.00 mg, 165.31 μmol, 59.03% yield, 96% purity) as a white solid.

LCMS: 378 [M+1]

Step 2.8-[(dimethylamino)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.A mixture oftert-butyl8-[(dimethylamino)methyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(55.00 mg, 145.70 mol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.69 g,14.86 mmol, 1.10 mL, 101.97 eq) and then the mixture was stirred at 20°C. for 1 hour under N2 atmosphere. TLC showed the starting material wasconsumed completely, a new spot appeared. The mixture was concentratedin vacuum to afford the title compound (57.00 mg, 145.63 μmol, 99.96%yield, TFA) as yellow oil, which was used directly for next step.

Step 3.N-(3-chloro-4-fluorophenvl)-8-((dimethylamino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.A mixture of8-[(dimethylamino)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(57.00 mg, 145.63 μmol, 1.00 eq, TFA), phenylN-(3-amino-4-fluoro-phenyl)carbamate (43.03 mg, 174.76 μmol, 1.20 eq),TEA (29.47 mg, 291.27 μmol, 40.37 μL, 2.00 eq) in DCM (5.00 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 20° C. for 16 hour under N2 atmosphere. LCMS showed thestarting material was consumed completely, desired product was major.The mixture was poured into water (10 mL) and stirred at 5 min. Theaqueous phase was extracted with DCM (5 mL*2). The combined organicphase was washed with brine (10 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byPrep-HPLC (HCl) to afford the title compound (59.00 mg, 130.11 μmol,89.34% yield, 99% purity) as a white solid. LCMS: 449/451 [M+1]. H NMR(400 MHz, CDCl₃) δ 7.57-7.63 (m, 1H), 7.15-7.22 (m, 1H), 7.02-7.10 (m,1H), 6.51-6.57 (m, 1H), 4.58-4.77 (m, 2H), 4.46-4.56 (m, 1H), 4.31 (s,1H), 3.84-3.89 (m, 3H), 3.47-3.61 (m, 1H), 3.25 (s, 3H), 3.12-3.20 (m,1H), 3.04 (m, 2H), 2.83-2.92 (m, 6H), 2.80-2.86 (m, 2H).

Compound 066:N-(3-chloro-4-fluorophenyl)-8-((3,3-difluoropyrrolidin-1-yl)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-[(3,3-difluoropyrrolidin-1-yl)methyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of tert-butyl10-methyl-8-(methylsulfonyloxymethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Compound 064, product from Step 2, 20.00 mg, 46.67 μmol, 1.00 eq),3,3-difluoropyrrolidine (49.99 mg, 466.74 μmol, 10.00 eq) in DMSO (1.00mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 88° C. for 16 hr under N2 atmosphere. TLC showed thestarting material/desired product/byproduct=3/2/1. Then3,3-difluoropyrrolidine (49.99 mg, 466.74 μmol, 10.00 eq) was added tothe mixture, and the mixture was stirred at 90° C. for 16 hr. TLC showedthe starting material was consumed completely, desiredproduct/byproduct=3/1. The mixture was poured into water (10 mL) andstirred at 5 min. The aqueous phase was extracted with ethyl acetate (5mL*2). The combined organic phase was washed with brine (10 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by Prep-TLC (DCM/MeOH=10/1) to afford the title compound(8.00 mg, 16.20 μmol, 34.71% yield, 89% purity) as a white solid.

LCMS: 440 [M+1].

Step 2.8-[(3,3-difluoropyrrolidin-1-yl)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.A mixture oftert-butyl8-[(3,3-difluoropyrrolidin-1-yl)methyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(8.00 mg, 18.20 mol, 1.00 eq) in DCM (2.00 mL) was added TFA (821.32 mg,7.20 mmol, 533.32 μL, 395.73 eq), and then the mixture was stirred at20° C. for 1 hour. TLC showed the starting material was consumedcompletely, and a new spot formed. The mixture was concentrated invacuum to afford the title compound (8.25 mg, 18.20 μmol, 100.00% yield,TFA) as a yellow oil, which was used directly for next step.

Step 3.N-(3-chloro-4-fluorophenyl)-8-((3,3-difluoropyrrolidin-1-yl)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of8-[(3,3-difluoropyrrolidin-1-yl)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(8.25 mg, 18.20 μmol, 1.00 eq, TFA), phenylN-(3-chloro-4-fluoro-phenyl)carbamate (5.32 mg, 20.01 μmol, 1.10 eq),TEA (3.68 mg, 36.39 μmol, 5.04 μL, 2.00 eq) in DCM (3.00 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 20° C. for 16 hours under N2 atmosphere. LCMS showed thestarting material was consumed completely, and the desired product wasmajor. The mixture was poured into water (10 mL) and extracted with DCM(5 mL*2). The combined organic phase was washed with brine (10 mL),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by Prep-HPLC (HCl) to afford the title compound(8.50 mg, 16.47 μmol, 90.49% yield, 99% purity) as a light yellow solid.LCMS: 511/513 [M+1].

¹H NMR (400 MHz, METHANOL-d₄) δ=7.58 (dd, J=2.6, 6.7 Hz, 1H), 7.31-7.25(m, 1H), 7.14 (s, 1H), 4.68 (d, J=3.0 Hz, 2H), 4.56-4.47 (m, 1H),4.36-4.27 (m, 1H), 4.04-3.53 (m, 7H), 3.35 (br s, 3H), 3.19 (d, J=1.6Hz, 3H), 3.09-2.97 (m, 1H), 2.82 (s, 4H).

Compound 067:N-(3-cyano-4-fluorophenyl)-8-((3,3-difluoropyrrolidin-1-yl)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

A mixture of8-[(3,3-difluoropyrrolidin-1-yl)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(Compound 066, product from Step 2, 62.00 mg, 136.74 μmol, 1.00 eq,TFA), Et₃N (69.18 mg, 683.70 mol, 94.77 μL, 5.00 eq) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (42.04 mg, 164.09 μmol, 1.20 eq) inDCM (6.00 mL) was stirred at 30° C. for 2 h. LCMS indicated the startingmaterial was consumed completely and major desired product. The mixturewas concentrated in vacuo, which was purified by prep-HPLC (FA) toafford (43.00 mg, 81.46 μmol, 59.57% yield, 95% purity) as yellow solid.LCMS: 502[M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (m, 1H), 7.60 (m, 1H),7.13 (t, J=8.74 Hz, 1H), 6.93 (s, 1H), 4.68 (s, 2H), 4.41 (m, 1H), 4.13(d, J=5.87 Hz, 1H), 3.87 (m, 2H), 3.46 (m, 1H), 3.26-3.37 (m, 1H), 3.18(s, 3H), 2.93 (m, 2H), 2.73-2.87 (m, 4H), 2.56-2.66 (m, 1H), 2.47-2.55(m, 2H), 2.30 (m, 2H).

Compound 068:8-((3,3-difluoropyrrolidin-1-yl)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

A mixture of8-[(3,3-difluoropyrrolidin-1-yl)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(Compound 066, product from Step 2, 62.00 mg, 136.74 mol, 1.00 eq, TFA),Et₃N (69.18 mg, 683.70 μmol, 94.77 μL, 5.00 eq) and phenylN-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (49.10 mg, 164.09 mol,1.20 eq) in DCM (6.00 mL) was stirred at 30° C. for 2 h. LCMS indicatedthe starting material was consumed completely and major desired product.The mixture was concentrated in vacuo, which was purified by prep-HPLC(FA) to afford the title compound (42.00 mg, 76.37 mol, 55.85% yield,99% purity) as white solid. LCMS: 545 [M+1 ¹H NMR (400 MHz, CDCl₃) δ7.70 (m, 1H), 7.57-7.64 (m, 1H), 7.11-7.16 (m, 1H), 6.83 (s, 1H), 4.71(s, 2H), 4.42 (m, 1H), 4.13 (m, 1H), 3.89 (m, 2H), 3.42-3.54 (m, 1H),3.27-3.39 (m, 1H), 3.19 (s, 3H), 2.95 (m, 2H), 2.86 (m, 4H),2.58-2.69(m, 1H), 2.49-2.56 (m, 2H), 2.32 (m, 2H).

Compound 069:N-(3-chloro-4-fluorophenyl)-10-methyl-1-oxo-8-(pyrrolidin-1-ylmethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl10-methyl-11-oxo-8-(pyrrolidin-1-ylmethyl)-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][14]diazepine-2-carboxylate.To a solution of tert-butyl10-methyl-8-(methylsulfonyloxymethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Compound 064, product from Step 2, 150.00 mg, 350.06 μmol, 1.00 eq) inDMSO (3.00 mL) was added pyrrolidine (248.96 mg, 3.50 mmol, 292.89 μL,10.00 eq), the mixture was stirred at 88° C. for 16 h. The reactionmixture was diluted with brine (40 mL) and extracted with EtOAc (30mL*2). The combined organic was washed with H₂O (60 mL*3), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC (DCM: MeOH=10:1) to afford the title compound(91.00 mg, 221.01 mol, 63.13% yield, 98% purity) as yellow oil, whichwas used directly for the next step.

LCMS: 404 [M+1].

Step 2.10-methyl-8-(pyrrolidin-1-ylmethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl10-methyl-11-oxo-8-(pyrrolidin-1-ylmethyl)-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(91.00 mg, 225.52 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.96 g,34.76 mmol, 2.57 mL, 154.14 eq), the mixture was stirred at 25° C. for 1h. The mixture was directly evaporated to afford the title compound(94.14 mg, 225.53 μmol, 100.00% yield, TFA) as yellow oil, which wasused directly for the next step.

LCMS: 304 [M+1].

Step 3.N-(3-chloro-4-fluorophenvl)-10-methyl-1-oxo-8-(pyrrolidin-1-ylmethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of10-methyl-8-(pyrrolidin-1-ylmethyl)-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(94.14 mg, 225.53 μmol, 1.00 eq, TFA) and Et₃N (114.11 mg, 1.13 mmol,156.31 μL, 5.00 eq) in DCM (3.00 mL) was added phenylN-(3-chloro-4-fluoro-phenyl)carbamate (59.92 mg, 225.53 μmol, 1.00 eq),the mixture was stirred at 25° C. for 16 h. The mixture was concentratedunder reduced pressure. The residue was purified by prep-HPLC(Base) toafford the title compound (61.00 mg, 127.15 μmol, 56.38% yield, 99%purity) as white solid. LCMS: 475/477 [M+1]. H NMR (400 MHz, CDCl₃) δ7.58-7.61 (m, 1H), 7.17-7.19 (m, 1H), 7.03-7.07 (m, 1H), 6.61 (s, 1H),4.67 (s, 2H), 4.39-4.44 (m, 1H), 4.0-4.2 (m, 1H), 3.84-3.87 (m, 2H),3.36-3.45 (m, 1H), 3.34-3.35 (m, 1H), 3.17 (s, 3H), 2.82-2.85 (m, 2H),2.65-2.67 (m, 1H), 2.48-2.55 (m, 6H), 1.79 (m, 4H).

Compound 070:8-(aminomethyl)-N-(3-chloro-4-fluorophenvl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.8-(azidomethyl)-N-(3-chloro-4-fluoro-phenyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.A mixture of[2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]methylmethanesulfonate(80.00 mg, 160.02 μmol, 1.00 eq) in DMF (5.00 mL) was added NaN₃ (20.81mg, 320.04 μmol, 11.25 μL, 2.00 eq) at 0° C. under N₂, and then themixture was stirred at 50° C. for 16 hr under N2 atmosphere. LCMS showedstarting material/desired product=1/8. Then NaN₃ (20.81 mg, 320.04 μmol,11.25 μL, 2.00 eq) was added to the mixture at 0° C. under N₂, and themixture was stirred at 50° C. for another 16 hr. The mixture was dilutedwith EtOAc (20 mL) and washed with brine (20 mL*3). The organic phasewas dried over Na₂SO₄, filtered and concentrated in vacuum to afford thetitle compound (50.00 mg, 111.89 μmol, 69.92% yield) as a yellow oil,which was used directly for next step.

LCMS: 447 [M+1].

Step 3.8-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of8-(azidomethyl)-N-(3-chloro-4-fluoro-phenyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(40.00 mg, 89.51 μmol, 1.00 eq), NH₄Cl (14.36 mg, 268.53 μmol, 9.39 μL,3.00 eq) and Zn (11.71 mg, 179.02 μmol, 2.00 eq) in EtOH (5.00 mL) andH₂O (500.00 uL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 30° C. for 16 hour under N2 atmosphere. LCMSshowed the starting material was consumed completely, desired productwas major. The mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by Prep-HPLC (FA) to afford the titlecompound (32.00 mg, 74.51 μmol, 83.24% yield, 98% purity) as a whitesolid. LCMS: 421 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.62 (m, 1H),7.17-7.23 (m, 1H), 7.05 (s, 1H), 6.60-6.64 (m, 1H), 4.67 (d, J=2.51 Hz,2H), 4.37-4.47 (m, 1H), 4.13-4.25 (m, 1H), 3.86 (d, J=6.90 Hz, 2H), 3.44(d, J=5.40 Hz, 1H), 3.38 (d, J=7.53 Hz, 1H), 3.19 (s, 3H), 2.83 (d,J=5.65 Hz, 4H), 2.43-2.57 (m, 1H).

Compound 071:(R)—N-(2-bromo-5-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 072,using phenyl (2-bromo-5-chloro-4-fluorophenyl)carbamate in Step 3. LCMS[M+1]: 534/536. ¹H NMR (400 MHz, CDCl₃) δ=8.32 (d, J=7.5 Hz, 1H), 7.35(d, J=8.0 Hz, 1H), 6.93-6.98 (m, 1H), 5.88-6.24 (m, 1H), 5.00-5.09 (m,1H), 4.91 (s, 1H), 4.35-4.53 (m, 3H), 3.79-4.07 (m, 2H), 3.59 (s, 2H),3.00-3.09 (m, 1H), 2.66-2.75 (m, 1H), 2.36 (s, 2H), 1.23 (d, J=6.9 Hz,3H).

Compound 072:(3R)—N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl(3R)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl(3R)-3-methyl-11-oxo-3,4,7,8,9,10-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (700.00 mg, 2.18 mmol,1.00 eq) in DMF (7.00 mL) was added NaH (261.60 mg, 6.54 mmol, 60%purity, 3.00 eq) at −10° C. The mixture was stirred at −10° C. for 30min. Then a solution of 2,2-difluoroethyl trifluoromethanesulfonate(1.40 g, 6.54 mmol, 3.00 eq) in DMF (800.00 uL) was added dropwise at−10° C. The mixture was stirred at 0° C. for 1 hr. TLC (PE:EtOAc=1:1)showed one main spot appeared. The mixture was added into ice-water (50mL) and extracted with EtOAc (50 mL*3). The combined organic layer waswashed with H₂O (50 mL*3), dried over Na₂SO₄, filtrated. The filtratewas concentrated in vacuum. The residue was purified by columnchromatography (PE:EtOAc=30% 50%) to afford the title compound (800.00mg, 2.08 mmol, 95.41% yield) as colorless oil.

Step 2.(3R)-10-(2,2-difluoroethyl)-3-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one. To a solution of tert-butyl(3R)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(350.00 mg, 910.46 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (7.70g, 67.53 mmol, 5.00 mL, 74.17 eq). The mixture was stirred at 20° C. for1 hr. TLC (PE:EtOAc=1:1) showed the starting material consumed. Themixture was concentrated in vacuum to afford the title compound (380.00mg, crude, TFA) as brown oil.

Step 3.(3R)—N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(3R)-10-(2,2-difluoroethyl)-3-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(55.00 mg, 138.08 μmol, 1.00 eq, TFA) and Et₃N (69.86 mg, 690.40 μmol,95.70 μL, 5.00 eq) in DCM (2.00 mL) was added phenylN-(3-chloro-4-fluoro-phenyl)carbamate (36.68 mg, 138.08 μmol, 1.00 eq).The mixture was stirred at 25° C. for 16 h. The mixture was directlyevaporated. The residue was purified by prep-HPLC (FA) to afford thetitle compound (31.70 mg, 69.33 μmol, 50.21% yield, 99.7% purity) aswhite solid. LCMS [M+1]: 456

Compounds 073, 074, 075, 076, 077, 078, and 071 were prepared in amanner analogous to Compound 072.

Compound 073:(R)-10-(2,2-difluoroethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 072,using phenyl (4-fluoro-3-(trifluoromethyl)phenyl)carbamate in Step 3.LCMS [M+1]: 489. ¹H NMR (400 MHz, CDCl₃) δ=7.65-7.71 (m, 1H), 7.56-7.63(m, 1H), 7.13 (s, 1H), 6.61 (s, 1H), 6.05 (s, 1H), 5.13 (m, 1H), 4.84(m, 1H), 4.38-4.51 (m, 3H), 3.81-4.07 (m, 2H), 3.55-3.68 (m, 2H), 3.03(m, 1H), 2.68 (m, 1H), 2.37 (m, 2H), 1.19 (d, J=6.8 Hz, 3H).

Compound 074:(R)—N-(3-bromo-4-fluorophenvl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 072,using phenyl (3-bromo-4-fluorophenyl)carbamate in Step 3. LCMS [M+1]:500/502. ¹H NMR (400 MHz, CDCl₃) δ=7.69-7.74 (m, 1H), 7.27-7.30 (m, 1H),7.04 (br d, J=2.4 Hz, 1H), 6.46-6.58 (m, 1H), 5.86-6.24 (m, 1H),5.05-5.18 (m, 1H), 4.82 (m, 1H), 4.35-4.52 (m, 3H), 3.77-4.08 (m, 2H),3.59-3.61 (m, 2H), 2.93-3.09 (m, 1H), 2.69 (s, 1H), 2.36 (m, 2H), 1.18(dd, J=2.2, 6.8 Hz, 3H).

Compound 075:(R)—N-(2-bromo-3-fluoropyridin-4-yl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 072,using phenyl (2-bromo-3-fluoropyridin-4-yl)carbamate in Step 3. LCMS[M+1]: 501. ¹H NMR (400 MHz, CDCl₃) δ=8.14-8.18 (m, 1H), 8.06 (d, J=5.5Hz, 1H), 6.96-7.07 (m, 1H), 5.87-6.23 (m, 1H), 5.00-5.10 ((m, 1H),4.85-4.96 ((m, 1H), 4.35-4.56 (m, 3H), 3.77-4.09 (m, 2H), 3.58-3.63 (m,2H), 2.99-3.10 (m, 1H), 2.66-2.77 (m, 1H), 2.31-2.44 (m, 2H), 1.23 (d,J=6.9 Hz, 3H).

Compound 076:(R)—N-(3-cyano-4-fluorophenvl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 072,using phenyl (3-cyano-4-fluorophenyl)carbamate in Step 3. LCMS [M+1]:446. ¹H NMR (400 MHz, CDCl₃) δ=7.78 (s, 1H), 7.58-7.65 (m, 1H), 7.13 (s,1H), 6.79-6.89 (m, 1H), 5.87-6.24 (m, 1H), 5.07-5.18 (m, 1H), 4.84-4.92(m, 1H), 4.39-4.51 (m, 3H), 3.93 (br s, 2H), 3.57-3.68 (m, 2H),2.96-3.08 (m, 1H), 2.66-2.77 (m, 1H), 2.32-2.44 (m, 2H), 1.19 (d, J=6.9Hz, 3H).

Compound 077:(R)-10-(2,2-difluoroethyl)-N-(4-fluoro-3-methylphenyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 072,using phenyl (4-fluoro-3-methylphenyl)carbamate in Step 3. LCMS [M+1]:435. ¹H NMR (400 MHz, CDCl₃) δ =7.24-7.27 (m, 1H), 7.08-7.16 (m, 1H),6.88-6.97 (m, 1H), 6.46 (s, 1H), 6.05 (s, 1H), 5.12 (s, 1H), 4.83-4.89(m, 1H), 4.35-4.50 (m, 3H), 3.80-4.05 (m, 2H), 3.52-3.69 (m, 2H),2.98-3.07 (m, 1H), 2.62-2.70 (m, 1H), 2.36 (s, 2H), 2.25 (d, J=1.5 Hz,3H), 1.18 (d, J=6.9 Hz, 3H).

Compound 078:(R)—N-(5-chloro-2,4-difluorophenyl)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 072,using phenyl (5-chloro-2,4-difluorophenyl)carbamate in Step 3. LCMS[M+1]: 474. ¹H NMR (400 MHz, CDCl₃) δ=8.19 (s, 1H), 6.95 (dd, J=8.5,10.6 Hz, 1H), 6.53-6.59 (m, 1H), 6.05 (s, 1H), 5.02-5.13 (m, 1H),4.80-4.91 (m, 1H), 4.44 (s, 3H), 3.78-4.08 (m, 2H), 3.49-3.69 (m, 2H),2.99-3.09 (m, 1H), 2.71 (s, 1H), 2.36 (br s, 2H), 1.21 (d, J=6.8 Hz,3H).

Compound 079_D1:(3R,8R*)—N-(3-chloro-4-fluorophenyl)-8-fluoro-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl(3R)-8-fluoro-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a solution of tert-butyl(3R)-8-hydroxy-3,8,10-trimethyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 18, 65.00 mg, 178.36 μmol, 1.00 eq) in DCM (5.00 mL) wasadded BAST (236.76 mg, 1.07 mmol, 234.42 μL, 6.00 eq) at −30° C. underN₂, and the mixture was stirred at 20° C. for 2 hours. TLC (PE:EtOAc=1:1) showed that starting material was consumed completely and twomain new spots formed. The mixture was diluted with 10 mL and extractedwith DCM (15 mL*3). The combined organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The combined residue of twobatches of reaction was purified by prep-TLC (PE:EtOAc=1:1) to give twodiastereomers of the title compound D1: 40.00 mg, 109.16 μmol, 30.60%yield and D2: 35.00 mg, 95.52 μmol, 26.78% yield as white solid.

Step 2.(3R)-8-fluoro-3,8,10-trimethyl-1,2,3,4,7,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one_D1.To a solution of tert-butyl(3R)-8-fluoro-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1(40.00 mg, 109.16 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (1.23 g,10.80 mmol, 799.73 μL, 98.95 eq) at 20° C. with stirring for 1 h. LC-MSshowed that reactant starting material was consumed completely anddesired product was detected. The mixture was directly evaporated invacuo to afford the title compound (45.00 mg, crude, TFA) as yellow oil.

The other diastereomer was made by an analogous method.

*Pure but unknown diastereomer D1.

Step 3.(3R,8R*)—N-(3-chloro-4-fluorophenvl)-8-fluoro-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(3R)-8-fluoro-3,8,10-trimethyl-1,2,3,4,7,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one_D1(50.00 mg, 131.46 μmol, 1.00 eq, TFA) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (38.42 mg, 144.61 μmol, 1.10 eq)in DCM (3.00 mL) was added TEA (106.42 mg, 1.05 mmol, 145.78 μL, 8.00eq) at 20° C. for 16 h. LC-MS indicated that reactant consumedcompletely and desired product was detected. The reaction mixture wasconcentrated in vacuo. The resulting residue was purified by prep-HPLC(FA) to afford the title compound (33.00 mg, 75.36 μmol, 57.33% yield,100% purity) as white solid.

LCMS: 438 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ=7.58 (dd, J=2.69, 6.48 Hz,1H), 7.14-7.22 (m, 1H), 7.00-7.10 (m, 1H), 6.52 (s, 1H), 5.10 (m, 1H),4.78 (d, J=15.65 Hz, 1H), 4.35-4.53 (m, 3H), 3.48 (m, 1H), 3.37-3.45 (m,1H), 3.18-3.26 (m, 3H), 2.94-3.06 (m, 1H), 2.68 (m, 1H), 1.51-1.59 (m,3H), 1.19 (d, J=6.85 Hz, 3H). 079_D2 was prepared by an analogousmethod.

Compound 079_D2:(3R,8S*)—N-(3-chloro-4-fluorophenvl)-8-fluoro-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound079_D1, *Pure but unknown diastereomer D2. LCMS: 438 [M+1]. ¹H NMR (400MHz, CDCl₃) δ=7.60 (dd, J=2.63, 6.54 Hz, 1H), 7.17-7.23 (m, 1H),7.03-7.09 (m, 1H), 6.60 (s, 1H), 5.13 (m, 1H), 4.88 (d, J=15.41 Hz, 1H),4.34-4.54 (m, 3H), 3.47-3.58 (m, 1H), 3.35-3.46 (m, 1H), 3.22 (s, 3H),3.03 (m, 1H), 2.66 (m, 1H), 1.55-1.62 (m, 3H), 1.18 (d, J=6.85 Hz, 3H).

Compound 080_D1:(3R,8S*)—N-(3-chloro-4-fluorophenyl)-3,8,10-trimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′;3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide

Step 1.(3R)-3,8,10-trimethyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl(3R)-3,8,10-trimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate (Intermediate 17,60.00 mg, 172.20 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (770.00mg, 6.75 mmol, 500.00 μL, 39.22 eq) at 20° C. with stirring for 1 h. TLC(PE: EtOAc=0:1) showed that starting material consumed completely andone main spot formed. The mixture was concentrated to afford the titlecompound (65.00 mg, crude, TFA) as yellow oil.

Step 2.(3R,8S*)—N-(3-chloro-4-fluorophenyl)-3,8,10-trimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide;*Pure but unknown diastereomer D1. To a solution of(3R)-3,8,10-trimethyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (65.00 mg, 179.38 μmol, 1.00 eq, TFA) andphenyl N-(3-chloro-4-fluoro-phenyl)carbamate (50.04 mg, 188.35 μmol,1.05 eq) in DCM (3.00 mL) was added TEA (145.22 mg, 1.44 mmol, 198.93μL, 8.00 eq) at 20° C. for 16 h. LCMS indicated that reactant 7 wasconsumed completely and desired product was detected. The residue wasdirectly evaporated. The residue was purified by prep-HPLC (FA),followed by SFC to give two diastereomers: 080_D1 (15.50 mg, 36.92 μmol,20.58% yield) as white solid and 080_D2 (17.24 mg, 40.24 μmol, 22.43%yield, 98% purity) as white solid.

SFC separation condition: Instrument: SFC 80; Column: AD-10 um; Mobilephase: A for CO₂ and B for EtOH (0.1% NH₃H₂O); Gradient: B 30%; Flowrate: 60 mL/min; Back pressure: 100 bar; Column temperature: 35° C.;Wavelength: 220 nm. LCMS: 420 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ=7.61 (dd,J=2.63, 6.54 Hz, 1H), 7.17-7.23 (m, 1H), 7.02-7.08 (m, 1H), 6.61 (s,1H), 5.14 (m, 1H), 4.81 (d, J=15.28 Hz, 1H), 4.39-4.49 (m, 2H),3.98-4.03 (m, 1H), 3.89-3.42 (m, 1H), 3.19 (s, 3H), 3.13-3.16 (m, 1H),3.02-3.08 (m, 1H), 2.61-2.70 (m, 2H), 1.17 (d, J=6.85 Hz, 3H), 1.12 (d,J=6.72 Hz, 3H).

Compound 080_D2:(3R,8R*)—N-(3-chloro-4-fluorophenvl)-3,8,10-trimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide

The title compound was prepared in a manner analogous to Compound 080D1,*Pure but unknown diastereomer D2._LCMS: 420 [M+1]. ¹H NMR (400 MHz,CDCl₃) δ=7.61 (dd, J=2.69, 6.60 Hz, 1H), 7.16-7.23 (m, 1H), 7.01-7.08(m, 1H), 6.59 (s, 1H), 5.14 (m, 1H), 4.81 (d, J=15.41 Hz, 1H), 4.40-4.50(m, 2H), 3.98 (m, 1H), 3.45-3.47 (m, 1H), 3.20 (s, 3H), 3.13-3.16 (m,1H), 3.01-3.08 (m, 1H), 2.58-2.69 (m, 2H), 1.17 (dd, J=6.91, 12.78 Hz,6H).

Compound 081:(3R,8S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide

Step 1.(3R,8S*)-8-(hydroxymethyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one.To a solution of tert-butyl(3R)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 16, 2.00 g, 4.72 mmol, 1.00 eq) in MeOH (20.00 mL) wasadded HCl/MeOH (4 M, 10.00 mL, 8.47 eq) at 25° C. with stirring for 3 h.TLC (PE: EtOAc=0:1) showed that reactant tert-butyl(3R)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylatewas consumed completely. The mixture was concentrated in vacuo. Theresidue with 92% purity was resolved by SFC (Analytic condition:AD-3S_4_5_40_3 ML Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobilephase: iso-propanol (0.05% DEA) in CO₂ from 5% to 40%. Flow rate: 3mL/min Wavelength: 220 nm. Separation condition: Instrument: SFC 80;Column: AD-5 um. Mobile phase: A for CO₂ and B for IPA (0.1% NH₃H₂O);Gradient: B 25%; Flow rate: 55 mL/min; Back pressure: 100 bar; Columntemperature: 35; Wavelength: 220 nm) to give both diastereomers:(3R,8S*)-8-(hydroxymethyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(520 mg) and(3R,8R*)-8-(hydroxymethyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(670 mg) as white solid.

Step 2.(3R,8S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide.To a solution of(3R,8S*)-8-(hydroxymethyl)-3,10-dimethyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (40.00 mg, 151.33 μmol, 1.00 eq) inDCM (3.00 mL) was added phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (54.34 mg, 181.60 μmol, 1.20 eq) and Et₃N (76.57 mg, 756.65μmol, 104.89 μL, 5.00 eq). The mixture was stirred at 25° C. for 16 h.The mixture was concentrated under reduced pressure. The resultingresidue was purified by prep-HPLC(FA) to afford (24.10 mg, 50.83 μmol,33.59% yield, 99% purity) as white solid. *Pure but unknowndiastereomer. LCMS: 470 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (m, 1H),7.55-7.64 (m, 1H), 7.12 (t, J=9.35 Hz, 1H), 6.82 (s, 1H), 5.14-5.17 (m,1H), 4.84-4.88 (m, 1H), 4.36-4.49 (m, 2H), 4.19-4.23 (m, 1H), 3.65-3.77(m, 2H), 3.32-3.54 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m, 1H), 2.61-2.77(m, 2H), 1.18 (d, J=6.90 Hz, 3H).

Compounds 082, 083, 084, 085, 086, 087, 088, 089, and 090 were preparedin a manner analogous to compound 081 from the correspondingdiastereomer.

Compound 081_D2:(3R,8R*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 470 [M+1] ¹H NMR (400 MHz, CDCl₃)δ 7.69-7.10 (m, 1H), 7.59-7.61 (m, 1H), 7.12 (t, J=9.41 Hz, 1H), 6.77(s, 1H), 5.15 (t, J=6.53 Hz, 1H), 4.80-4.84 (m, 1H), 4.36-4.52 (m, 2H),4.25-4.27 (m, 1H), 3.64-3.76 (m, 2H), 3.32-3.52 (m, 2H), 3.20 (s, 3H),3.00-3.04 (m, 1H), 2.61-2.78 (m, 2H), 1.19 (d, J=6.90 Hz, 3H).

Compound 082_D1:(3R,8S*)—N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-8-(hydroxymethyl-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS:488 [M+1] ¹H NMR (400 MHz, CDCl₃) δ8.38 (t, J=7.97 Hz, 1H), 6.99 (t, J=10.04 Hz, 1H), 6.66 (br d, J=2.89Hz, 1H), 5.10-5.30 (m, 1H), 4.84-4.88 (m, 1H), 4.39-4.52 (m, 2H),4.16-4.20 (m, 1H), 3.67-3.77 (m, 2H), 3.33-3.55 (m, 2H), 3.20 (s, 3H),3.00-3.04 (m, 1H), 2.63-2.76 (m, 2H), 1.20 (d, J=6.90 Hz, 3H).

Compound 082_D2:(3R,8R*)—N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4.7.8.9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound081*Pure but unknown diastereomer. LCMS:488 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 8.38 (t, J=8.03 Hz, 1H), 6.99 (t, J=10.10 Hz, 1H), 6.63 (s,1H), 5.08-5.12 (m, 1H), 4.81-4.85 (m, 1H), 4.52 (d, J=15.56 Hz, 1H),4.22-4.45 (m, 2H), 3.60-3.76 (m, 2H), 3.30-3.50 (m, 2H), 3.20 (s, 3H),3.00-3.05 (m, 1H), 2.61-2.79 (m, 2H), 1.21 (d, J=6.90 Hz, 3H).

Compound 083_D1:(3R,8S*)—N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound081*Pure but unknown diastereomer. LCMS: 488 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 8.17-8.23 (m, 1H), 6.98 (t, J=9.16 Hz, 1H), 6.67 (s, 1H),5.08-5.10 (m, 1H), 4.85-4.89 (m, 1H), 4.39-4.53 (m, 2H), 4.17-4.19 (m,1H), 3.66-3.78 (m, 2H), 3.32-3.55 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m,16.06 Hz, 1H), 2.63-2.76 (m, 2H), 1.20 (d, J=6.90 Hz, 3H).

Compound 083_D2:(3R,8R*)—N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound081*Pure but unknown diastereomer. LCMS: 488 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 8.19-8.25 (m, 1H), 6.99 (t, J=9.41 Hz, 1H), 6.61 (s, 1H),5.06-5.09 (m, 1H), 4.83-4.86 (m, 1H), 4.49-4.51 (m, 1H), 4.22-4.44 (m,2H), 3.62-3.74 (m, 2H), 3.31-3.50 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m,1H), 2.64-2.77 (m, 2H), 1.21 (d, J=6.85 Hz, 3H).

Compound 084_D1:(3R,8S*)—N-(3-bromo-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound081*Pure but unknown diastereomer. LCMS: 498/500 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 7.89-7.95 (m, 1H), 6.94 (t, J=7.6 Hz, 1H), 6.58 (s, 1H),5.08-5.10 (m 1H), 4.85-4.88 (m, 1H), 4.38-4.53 (m, 2H), 4.14-4.18 (m,1H), 3.66-3.79 (m, 2H), 3.32-3.56 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m,1H), 2.61-2.76 (m, 2H), 1.20 (d, J=6.90 Hz, 3H).

Compound 084_D2:(3R,8R*)—N-(3-bromo-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4.7.8.9.1011-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 498/500 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 7.90-7.96 (m, 1H), 6.91-6.96 (m, 1H), 6.55 (s, 1H), 5.02-5.13(m, 1H), 4.82-4.86 (m, 1H), 4.49-4.53 (m, 1H), 4.22-4.45 (m, 2H),3.62-3.74 (m, 2H), 3.30-3.50 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m, 1H),2.63-2.77 (m, 2H), 1.21 (d, J=6.90 Hz, 3H).

Compound 085_D1:(3R,8S*)—N-(5-bromo-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4.7.8.9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound081,*Pure but unknown diastereomer. LCMS: 498/500 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 8.23-8.39 (m, 1H), 6.93 (t, J=7.97 Hz, 1H), 6.57 (s, 1H),5.09-5.11 (m 1H), 4.82-4.86 (m, 1H), 4.37-4.52 (m, 2H), 4.17-4.19 (m,1H), 3.64-3.80 (m, 2H), 3.33-3.54 (m, 2H), 3.20 (s, 3H), 2.98-3.02 (m,1H), 2.63-2.77 (m, 2H), 1.20 (d, J=6.78 Hz, 3H).

Compound 085_D2:(3R,8R*)—N-(5-bromo-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4.7.8.9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound081,*Pure but unknown diastereomer. LCMS: 498/500 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 8.25-8.37 (m, 1H), 6.91-6.95 (m, 1H), 6.55 (s, 1H), 5.09-5.11(m, 1H), 4.79-4.83 (m, 1H), 4.48-4.52 (m, 1H), 4.20-4.44 (m, 2H),3.63-3.73 (m, 2H), 3.29-3.51 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m, 1H),2.62-2.77 (m, 2H), 1.20 (d, J=6.90 Hz, 3H).

Compound 086_D1:(3R,8S*)—N-(3-bromo-4-fluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound081,*Pure but unknown diastereomer. LCMS: 480/482 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 7.73-7.75 (m, 1H), 7.24-7.27 (m, 1H), 6.95-7.09 (m, 1H), 6.65(s, 1H), 5.06-5.20 (m, 1H), 4.83 (d, J=15.18 Hz, 1H), 4.36-4.48 (m, 2H),4.20-4.22 (m, 1H), 3.70-3.74 (m, 2H), 3.33-3.54 (m, 2H), 3.20 (s, 3H),3.00-3.05 (m, 1H), 2.58-2.78 (m, 2H), 1.18 (d, J=6.90 Hz, 3H).

Compound 086_D2:(3R,8R*)—N-(3-bromo-4-fluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 480/482 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 7.72-7.75 (m, 1H), 7.25-7.26 (m, 1H), 7.04 (t, J=8.53 Hz, 1H),6.61 (s, 1H), 5.13-5.15 (m, 1H), 4.78-4.81 (m, 1H), 4.37-4.51 (m, 2H),4.24-4.27 (m, 1H), 3.62-3.75 (m, 2H), 3.30-3.50 (m, 2H), 3.20 (s, 3H),3.01-3.04 (m, 1H), 2.59-2.79 (m, 2H), 1.18 (d, J=6.78 Hz, 3H).

Compound 087_D1:(3R,8S*)—N-(3-cyano-4-fluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 427 [M+1] ¹H NMR (400 MHz, CDCl₃)δ 7.79-7.81 (m, 1H), 7.59-7.61 (m, 1H), 7.07-7.17 (m, 1H), 6.93 (s, 1H),5.07-5.19 (m, 1H), 4.86 (d, J=15.43 Hz, 1H), 4.36-4.49 (m, 2H),4.19-4.24 (m, 1H), 3.66-3.80 (m, 2H), 3.30-3.55 (m, 2H), 3.20 (s, 3H),3.01-3.05 (m, 1H), 2.58-2.76 (m, 2H), 1.18 (d, J=6.90 Hz, 3H).

Compound 087_D2:(3R,8R*)—N-(3-cyano-4-fluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 427 [M+1] ¹H NMR (400 MHz, CDCl₃)δ 7.78-7.80 (m, 1H), 7.59-7.62 (m, 1H), 7.13 (t, J=8.68 Hz, 1H), 6.88(s, 1H), 5.13-5.15 (m, 1H), 4.80-4.85 (m, 1H), 4.37-4.53 (m, 2H),4.22-4.25 (m, 1H), 3.62-3.76 (m, 2H), 3.31-3.53 (m, 2H), 3.20 (s, 3H),3.00-3.03 (m, 1H), 2.62-2.76 (m, 2H), 1.19 (d, J=6.97 Hz, 3H).

Compound 088_D1:(3R,8S*)—N-(3-cyano-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 445 [M+1] ¹H NMR (400 MHz, CDCl₃)δ 8.23-8.29 (m, 1H), 7.01 (t, J=7.97 Hz, 1H), 6.69 (s, 1H), 5.08 (m,1H), 4.86-4.89 (m, 1H), 4.38-4.54 (m, 2H), 4.18-4.20 (m, 1H), 3.65-0.78(m, 2H), 3.33-3.55 (m, 2H), 3.20 (s, 3H), 3.01-3.06 (m, 1H), 2.62-2.78(m, 2H), 1.21 (d, J=6.90 Hz, 3H).

Compound 088_D2:(3R,8R*)—N-(3-cyano-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 445 [M+1] ¹H NMR (400 MHz, CDCl₃)δ 8.24-8.30 (m, 1H), 6.99-7.27 (m, 1H), 6.63 (s, 1H), 5.07-5.09 (m, 1H),4.82-4.86 (m, 1H), 4.50-4.54 (m, 1H), 4.20-4.45 (m, 2H), 3.64-3.75 (m,2H), 3.31-3.52 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m, 1H), 2.61-2.76 (m,2H), 1.21 (d, J=6.90 Hz, 3H).

Compound 089_D1:(3R,8S*)—N-(3-choro-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound081,*Pure but unknown diastereomer. LCMS: 454/456 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 7.83-7.89 (m, 1H), 6.92-6.97 (m, 9.25 Hz, 1H), 6.58 (s, 1H),5.08-5.10 (m, 1H), 4.85-4.89 (m, 1H), 4.39-4.54 (m, 2H), 4.17-4.19 (m,1H), 3.64-3.78 (m, 2H), 3.33-3.56 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m,1H), 2.61-2.76 (m, 2H), 1.20 (d, J=6.90 Hz, 3H).

Compound 089_D2:(3R,8R*)—N-(3-chloro-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4.7.8.9.1011-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 454/456 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 7.84-7.90 (m, 1H), 6.92-6.97 (m, 1H), 6.55 (s, 1H), 5.01-5.14(m, 1H), 4.82-4.86 (m, 1H), 4.49-4.53 (m, 1H), 4.22-4.44 (m, 2H),3.67-3.69 (m, 2H), 3.30-3.49 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m, 1H),2.62-2.76 (m, 2H), 1.21 (d, J=6.85 Hz, 3H).

Compound 090_D1:(3R,8S*)—N-(5-chloro-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4.7.8.9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 454/456 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 8.18 (t, J=8.09 Hz, 1H), 6.92-6.97 (m, 1H), 6.58 (s, 1H),5.08-5.10 (m, 1H), 4.83-4.87 (m, 1H), 4.38-4.54 (m, 2H), 4.17-4.19 (m,1H), 3.65-3.79 (m, 2H), 3.32-3.57 (m, 2H), 3.20 (s, 3H), 3.01-3.04 (m,1H), 2.61-2.74 (m, 2H), 1.20 (d, J=6.78 Hz, 3H).

Compound 090_D2:(3R,8R*)—N-(5-chloro-2,4-difluorophenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4.7.8.9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 081,*Pure but unknown diastereomer. LCMS: 454/456 [M+1] ¹H NMR (400 MHz,CDCl₃) δ 8.16-8.20 (m, 1H), 6.92-6.97 (m, 1H), 6.55 (s, 1H), 5.08-5.12m, 1H), 4.80-4.84 (m, 1H), 4.48-4.52 (m, 1H), 4.22-4.43 (m, 2H),3.60-3.75 (m, 2H), 3.30-3.50 (m, 2H), 3.20 (s, 3H), 3.01-3.05 (m, 1H),2.62-2.77 (m, 2H), 1.20 (d, J=6.90 Hz, 3H).

Compound 091:N-(3-chloro-4-fluorophenyl)-8-(2,2-difluoroethyl)-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. 2-tert-butyl 8-ethyl8-(2,2-difluoroethyl)-10-methyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate.To a solution of 2-tert-butyl 8-ethyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate(Intermediate 14, 400.00 mg, 1.02 mmol, 1.00 eq) in THF (8.00 mL) wasadded LDA (1 M, 3.06 mL, 3.00 eq) at −65° C. under N₂, followed by2,2-difluoroethyl trifluoromethanesulfonate (1.09 g, 5.10 mmol, 5.00 eq)after 0.5 h, and the mixture was stirred at 25° C. for another 5 h. LCMSindicated 45% desired product and multiple peaks. The mixture combinewith another batch and was diluted with EtOAc (60 mL) and washed withHCl (1 M, 60 mL). The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo, which was purified by prep-HPLC(FA) to afford thetitle compound (185.00 mg, 405.28 μmol, 39.73% yield) as yellow solid.LCMS: 457 [M+1].

Step 2. ethyl8-(2,2-difluoroethyl)-10-methyl-11-oxo-1,2,3,4,7,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate.To a solution of 2-tert-butyl 8-ethyl8-(2,2-difluoroethyl)-10-methyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate(215.00 mg, 471.00 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (4.62g, 40.52 mmol, 3.00 mL, 86.03 eq), and the mixture was stirred at 25° C.under N₂ for 1 h. TLC showed no starting material and one major new spotwas detected. The mixture was concentrated in vacuo to afford the titlecompound (221.00 mg, 469.82 μmol, 99.75% yield, TFA) as yellow oil,which was used directly for the next step.

Step 3. ethyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-8-(2,2-difluoroethyl)-10-methyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate.A mixture of ethyl8-(2,2-difluoroethyl)-10-methyl-1-oxo-1,2,3,4,7,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate (221.00 mg,469.82 μmol, 1.00 eq, TFA), Et₃N (237.71 mg, 2.35 mmol, 325.63 μL, 5.00eq) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (137.30 mg, 516.80μmol, 1.10 eq) in DCM (10.00 mL) was stirred at 25° C. for 16 h. LCMSindicated the starting material was consumed completely and majordesired product. The mixture was diluted with DCM (40 mL) and washedwith HCl (1 M, 40 mL). The organic phase was dried over Na₂SO₄, filteredand concentrated in vacuo, which was purified by silica gel column toafford the title compound (195.00 mg, 361.99 mol, 77.05% yield, 98%purity) as yellow solid.

LCMS: 528 [M+1].

Step 4.N-(3-chloro-4-fluorophenyl)-8-(2,2-difluoroethyl)-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of ethyl2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-8-(2,2-difluoroethyl)-10-methyl-11-oxo-3,4,7,9-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate(90.00 mg, 170.48 mol, 1.00 eq) in THF (5.00 mL) was added LiBH₄ (11.14mg, 511.44 μmol, 3.00 eq) at 0° C. and the mixture was stirred at 25° C.for 2 h. LCMS indicated starting material consumed and desired productwas detected. The mixture was quenched with H₂O (30 mL) and extractedwith EtOAc (30 mL). The organic phase was dried over Na₂SO₄, filteredand concentrated in vacuo, which was purified by prep-HPLC(FA) to affordthe title compound (50.00 mg, 101.87 μmol, 59.76% yield, 99% purity) aswhite solid. LCMS: 486 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.61 (m,1H), 7.21-7.28 (m, 1H), 7.05-7.09 (t, J=8.8 Hz, 1H), 6.68 (s, 1H),6.06-6.34 (m, 1H), 4.68-4.73 (m, 2H), 4.24-4.28 (m, 1H), 4.05-4.09 (m,1H), 3.85-3.88 (m, 2H), 3.67-3.70 (m, 2H), 3.19-3.28 (m, 5H), 2.84-2.87(m, 2H), 2.05-2.09 (m, 2H).

Compound 092_D1:(3R,8R*)—N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-8-(hydroxymethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. ethyl(3R)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate.To a solution of 2-tert-butyl 8-ethyl(3R)-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate(Intermediate 20, 130.00 mg, 284.79 μmol, 1.00 eq) in DCM (3.00 mL) wasadded TFA (4.62 g, 40.52 mmol, 3.00 mL, 142.28 eq), and the mixture wasstirred at 25° C. under N₂ for 1 h. TLC showed no starting material andone major new spot was detected. The mixture was concentrated in vacuoto afford the title compound (133.00 mg, 282.74 μmol, 99.28% yield, TFA)as yellow oil, which was used directly for the next step.

Step 2. ethyl(16S)-12-chloro-26-(2,2-difluoroethyl)-11-fluoro-18,19-dioxo-22,23,24,25,26-pentazapentacyclodocosa-1(11),2(12),9,13(22),14-pentaene-17-carboxylate.A mixture of ethyl(3R)-10-(2,2-difluoroethyl)-3-methyl-1-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate(133.00 mg, 282.74 μmol, 1.00 eq, TFA), Et₃N (143.05 mg, 1.41 mmol,195.96 μL, 5.00 eq) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate(90.14 mg, 339.29 mol, 1.20 eq) in DCM (10.00 mL) was stirred at 25° C.for 16 h. TLC indicated the starting material was consumed completelyand major desired product. The mixture was diluted with DCM (40 mL) andwashed with HCl (1 M, 40 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo, which was purified by silica gelcolumn to afford the title compound (120.00 mg, 229.74 μmol, 81.26%yield, 98% purity) as yellow solid. LCMS: 528 [M+1].

Step 3.(3R,8R*)—N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-8-(hydroxymethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide;*Pure but unknown diastereomer D1. To a solution of ethyl(3R)-2-[(3-chloro-4-fluoro-phenyl)carbamoyl]-10-(2,2-difluoroethyl)-3-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylate(30.00 mg, 56.83 μmol, 1.00 eq) in THF (2.00 mL) was added LiBH₄ (3.71mg, 170.48 μmol, 3.00 eq) at 0° C. and the mixture was stirred at 25° C.for 2 h. LCMS showed no starting material and major desired product. Themixture was quenched with H₂O (20 mL) and extracted with EtOAc (30 mL).The organic phase was dried over Na₂SO₄, filtered and concentrated invacuo. The residue combined another batch (EW645-046) was purified byprep-TLC to give 10 mg of product, which was resolved by SFC(“AD-3S_3_5_40_3 ML Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobilephase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3 mL/minWavelength: 220 nm”), following by prep-HPLC (FA) to afford each 24 mgof the title compound.

LCMS: 486/488 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (m, 1H), 7.18-7.25(m, 1H), 7.02-7.11 (m, 1H), 6.59 (s, 1H), 5.91-6.28 (m, 1H), 5.13 (m,1H), 4.87 (m, 1H), 4.12-4.48 (m, 3H), 3.43-3.81 (m, 4H), 3.03 (m, 1H),2.58-2.80 (m, 1H), 1.18 (m, 3H).

Compound 092_D2:(3R,8S*)—N-(3-chloro-4-fluorophenvl)-10-(2,2-difluoroethyl)-8-(hydroxymethyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 092_D1was synthesized by an analogous method. *Pure but unknown diastereomerD2._LCMS: 486/488 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (m, 1H),7.17-7.25 (m, 1H), 7.04-7.12 (m, 1H), 6.51 (s, 1H), 5.90-6.29 (m, 1H),5.10 (s, 1H), 4.79 (m, 1H), 4.19-4.54 (m, 4H), 3.42-3.76 (m, 5H),2.99-3.09 (m, 1H), 2.71 (s, 2H), 1.21 (m, 3H).

Compound 93:8-(aminomethyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide

Step 1.8-(hydroxymethyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Compound 064, product from Step 1, 200.00 mg, 570.76 μmol, 1.00 eq) inDCM (2.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 47.33 eq) at0° C. The mixture was stirred at 25° C. for 1 h. LCMS showed that thereactant was consumed completely and the desired product was major. Themixture was concentrated under reduced pressure to afford the titlecompound (207.00 mg, 568.18 μmol, 99.55% yield, TFA) as yellow oil whichwas used directly for the next step.

Step 2.N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide.To a solution of4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (100.00 mg, 273.01 μmol,1.00 eq, TFA) in DCM (3.00 mL) was added phenylN-[4-fluoro-3-(trifluoromethyl) phenyl]carbamate (98.03 mg, 327.61 μmol,1.20 eq) and Et₃N (138.13 mg, 1.37 mmol, 189.22 μL, 5.00 eq). Themixture was stirred at 25° C. for 16 h. LCMS showed the reactant wasconsumed completely and the desired product was major. The mixture wasdiluted with Ethyl acetate (30 mL) and extracted with brine (30 mL*3).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure which was purified by prep-TLC toafford the title compound (120.00 mg, 259.74 μmol, 95.14% yield, 99%purity) as white solid.

Step 3.[2-[[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]methylmethanesulfonate. To a solution ofN-[4-fluoro-3-(trifluoromethyl)phenyl]-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(120.00 mg, 263.50 μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (133.32mg, 1.32 mmol, 182.63 μL, 5.00 eq) and MsCl (90.55 mg, 790.50 μmol,61.18 μL, 3.00 eq) at 0° C. The mixture was stirred at 25° C. for 2 hr.TLC (Dichloromethane:Methanol=10:1) showed the reaction was completed.The mixture was poured into water (20 mL), and extracted with ethylacetate (20 mL*2). The organic layer was washed with brine (10 mL),dried over anhydrous Na₂SO₄ and concentrated in vacuum to afford thetitle compound (140.00 mg, 262.42 μmol, 99.59% yield) as colorless oil.

Step 4.8-(azidomethyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a solution of[2-[[4-fluoro-3-(trifluoromethyl)phenyl]carbamoyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]methylmethanesulfonate (140.00 mg, 262.42 μmol, 1.00 eq) in DMF (3.00 mL) wasadded NaN3 (68.24 mg, 1.05 mmol, 4.00 eq) at 0° C. The mixture wasstirred at 50° C. for 16 hr. LCMS showed the reaction was completed. Thereaction mixture was quenched by addition water (20 mL), and thenextracted with ethyl acetate (20 mL*3). The combined organic layers werewashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound (120.00mg, 249.78 mol, 95.18% yield) as colorless oil.

Step 5.8-(aminomethyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamideandN-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-8-(methylaminomethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide:To a solution of8-(azidomethyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(120.00 mg, 249.78 μmol, 1.00 eq) in MeOH (5.00 mL) was added Pd/C(20.00 mg, 10% purity). The mixture was stirred under H₂ (15 PSi) at 25°C. for 3 hr. TLC showed the reactant consumed, LCMS showed 32% Compound093 and 39% Compound 094(N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-8-(methylaminomethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide).The mixture was filtered and the filtrate was concentrated in vacuumwhich was purified by prep-HPLC to afford Compound 93:8-(aminomethyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(20.00 mg, 41.81 μmol, 16.74% yield, 95% purity) as white solid andCompound 94:N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-8-(methylaminomethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(9.00 mg, 18.25 μmol, 7.31% yield, 95% purity) was obtained as whitesolid.

LCMS: 455 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J=2.63, 6.05 Hz,1H), 7.56-7.63 (m, 1H), 7.12 (t, J=9.41 Hz, 1H), 6.86 (s, 1H), 4.62-4.78(m, 2H), 4.40-4.44 (m, 1H), 4.21-4.38 (m, 1H), 3.78-3.96 (m, 2H),3.32-3.55 (m, 2H), 3.19 (s, 3H), 2.71-2.88 (m, 4H), 2.38-2.59 (m, 1H).

Compound 94:N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-8-(methylaminomethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide

LCMS: 469 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J=2.70, 6.09 Hz,1H), 7.56-7.64 (m, 1H), 7.11 (t, J=9.35 Hz, 1H), 6.98 (s, 1H), 4.57-4.75(m, 2H), 4.40-4.42 (m, 1H), 4.13-4.15 (m, 1H), 3.78-3.95 (m, 2H),3.30-3.53 (m, 2H), 3.17 (s, 3H), 2.84 (t, J=5.77 Hz, 2H), 2.53-2.75 (m,3H), 2.46 (s, 3H).

Compound 095:8-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.N-(3-cyano-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide.To a solution of4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (Compound 093, product fromStep 1, 100.00 mg, 273.01 mol, 1.00 eq, TFA) in DCM (3.00 mL) was addedphenyl N-(3-cyano-4-fluoro-phenyl)carbamate (83.94 mg, 327.61 μmol, 1.20eq) and Et₃N (138.13 mg, 1.37 mmol, 189.22 μL, 5.00 eq). The mixture wasstirred at 25° C. for 16 h. LCMS showed that the reactant was consumedcompletely and the desired product was major. The mixture was dilutedwith Ethyl acetate (30 mL) and extracted with brine (30 mL*3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue which was purifiedby prep-TLC to afford the title compound (80.00 mg, 189.19 μmol, 69.30%yield, 98% purity) as white solid.

Step 2.[2-[(3-cyano-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]methylmethanesulfonate. To a solution ofN-(3-cyano-4-fluoro-phenyl)-8-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(80.00 mg, 193.98 μmol, 1.00 eq) in DCM (3.00 mL) was added TEA (98.14mg, 969.90 μmol, 134.44 μL, 5.00 eq) and MsCl (66.66 mg, 581.94 μmol,45.04 μL, 3.00 eq). The mixture was stirred at 20° C. for 4 hr. TLCshowed the reactant consumed and a mew spot detected. The mixture waspoured into water (10 mL), extracted with ethyl acetate (10 mL*3), theorganic layer was washed with brine (10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuum to afford the title compound(95.00 mg, 193.68 μmol, 99.84% yield) as white solid.

Step 3.8-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a solution of[2-[(3-cyano-4-fluoro-phenyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl]methylmethanesulfonate (100.00 mg, 203.87 μmol, 1.00 eq) in DMF (3.00 mL) wasadded NaN₃ (53.01 mg, 815.48 μmol, 4.00 eq) at 0° C. The mixture wasstirred at 50° C. for 16 hr. LCMS showed the reaction was completed. Thereaction mixture was quenched by addition water (20 mL), and extractedwith ethyl acetate (20 mL*3). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound (80.00mg, 182.89 μmol, 89.71% yield) as colorless oil.

Step 4.8-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a mixture of8-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(80.00 mg, 182.89 μmol, 1.00 eq) in EtOH (5.00 mL) and H₂O (500.00 uL)was added Zn (47.84 mg, 731.56 μmol, 4.00 eq) and NH₄Cl (58.70 mg, 1.10mmol, 38.37 μL, 6.00 eq). The mixture was stirred at 25° C. for 16 hr.LCMS showed the reactant consumed and the desired product detected. Themixture was filtered and the filtrate was purified by prep-HPLC toafford (30.00 mg, 69.27 μmol, 37.88% yield, 95% purity) as white solid.LCMS: 412 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (dd, J=2.75, 5.44 Hz,1H), 7.60 (ddd, J=2.87, 4.52, 9.11 Hz, 1H), 7.13 (t, J=8.74 Hz, 1H),6.93 (s, 1H), 4.58-4.75 (m, 2H), 4.40-4.42 (m, 1H), 4.18-4.20 (m, 1H),3.87 (t, J=5.87 Hz, 2H), 3.31-3.53 (m, 2H), 3.13-3.26 (m, 3H), 2.72-2.89(m, 4H), 2.39-2.57 (m, 1H).

Compound 096_E1:(R*)—N-(5-chloro-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.2-tert-butoxycarbonyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylicacid. To a mixture of 2-tert-butyl 8-ethyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2,8-dicarboxylate(Intermediate 14, 4.80 g, 12.23 mmol, 1.00 eq) in MeOH (20.00 mL) andH₂O (4.00 mL) was added NaOH (978.47 mg, 24.46 mmol, 2.00 eq) in oneportion. The mixture was stirred at 30° C. for 5 hours. LCMS and TLC(Dichloromethane:Methanol=10:1) showed the reaction was completed. Themixture was concentrated in vacuum to remove MeOH. The residue pouredinto water (10 mL) and stirred for 1 min. The aqueous phase wasextracted with DCM (30 mL*2). The aqueous phase was adjust to pH=3 with1N HCl and extracted with ethyl acetate (30 mL*2), The combined organicphase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum to afford the title compound (4.40g, 12.07 mmol, 98.73% yield, 100% purity) as white solid. LCMS[M+1]: 365

Step 2. tert-butyl 8-[methoxy(methyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a mixture of2-tert-butoxycarbonyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8-carboxylicacid (500.00 mg, 1.37 mmol, 1.00 eq) and N-methoxymethanaminehydrochloride (534.52 mg, 5.48 mmol, 4.00 eq) in THF (10.00 mL) wasadded T₃P (1.74 g, 2.74 mmol, 1.63 mL, 50% purity, 2.00 eq) and TEA(2.08 g, 20.55 mmol, 2.85 mL, 15.00 eq) in one portion under N₂. Themixture was stirred at 30° C. for 12 hours. LCMS and TLC(Dichloromethane:Methanol=10:1) showed the reaction was completed. Themixture was poured into water (15 mL) and stirred for 2 min. The aqueousphase was extracted with ethyl acetate (20 mL*2). The combined organicphase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography (Dichloromethane:Methanol=50:1-20:1) to afford thetitle compound (510.00 mg, 1.24 mmol, 90.45% yield, 99% purity) as whitesolid. LCMS[M+1]: 408.

Step 3. tert-butyl10-methyl-11-oxo-8-prop-2-enoyl-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a mixture of vinylmagnesium bromide (1 M, 4.91 mL, 5.00 eq) in THE(4.00 mL) was added tert-butyl8-[methoxy(methyl)carbamoyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(400.00 mg, 981.69 μmol, 1.00 eq) in THF (2.00 mL) drop-wise at −30° C.under N₂. The mixture was heated to 0° C. and stirred for 1 hours. LCMSand TLC (Ethyl acetate) showed the reaction was completed and thedesired product was detected. The mixture was poured into 1N HCl (30 mL)and stirred for 2 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuumto afford the title compound (288.00 mg, 769.17 μmol, 78.35% yield) asyellow solid. LCMS[M+1]: 375.

Step 4. tert-butyl8-(1-hydroxyallyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate_E1-E4.To a mixture of tert-butyl10-methyl-11-oxo-8-prop-2-enoyl-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(3.70 g, 9.88 mmol, 1.00 eq) in MeOH (100.00 mL) was added CeCl₃ (4.87g, 19.76 mmol, 1.24 mL, 2.00 eq) in one portion at 0° C. under N₂. Themixture was stirred at 0° C. for 15 min, then NaBH₄ (1.50 g, 39.52 mmol,4.00 eq) was added to the mixture. The mixture was heated to 30° C. andstirred for 2 hours. LCMS and TLC (Dichloromethane:Methanol=10:1) showedthe reaction was completed. The mixture was poured into water (20 mL)and concentrated in reduced pressure. The aqueous phase was extractedwith ethyl acetate (50 mL*3). The combined organic phase was washed withbrine (20 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by silica gel chromatography(Dichloromethane:Methanol=100/1-20:1) to afford racemic title compound(2.70 g, 6.74 mmol, 68.24% yield, 94% purity) as yellow solid, Which wasseparated by SFC (Analytical method: IC-3S_3_5_40_3 ML Column: ChiralpakIC-3 100×4.6 mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂from 5% to 40% Flow rate: 3 mL/min Wavelength: 220 nm. Separationmethod: Instrument: SFC 80; Column: IC-10 um; Mobile phase: A for CO₂and B for MeOH (0.1% NH₃H₂O); Gradient: B 35%; Flow rate: 60 mL/min;Back pressure: 100 bar; Column temperature: 350; Wavelength: 220 nm) togive four isomers: E1: 650 mg, E2: 640 mg, E3: 650 mg and E4: 650 mg.

Step 5. tert-butyl8-(1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate_E1.To a solution of tert-butyl8-(1-hydroxyallyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(550.00 mg, 1.46 mmol, 1.00 eq) in MeOH (20.00 mL) was added Pd/C(100.00 mg) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 30° C. for 5 hours LCMS showed the starting material was consumedcompletely. The reaction mixture was filtered and the filtrate wasconcentrated to afford the title compound (520.00 mg, 1.37 mmol, 94.11%yield) as yellow solid. LCMS[M+1]: 379.

Step 6.8-(1-hydroxypropyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one_E1.To a mixture of tert-butyl8-(1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(200.00 mg, 528.46 mol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g,27.01 mmol, 2.00 mL, 51.12 eq) in one portion at 30° C. under N₂. Themixture was stirred at 30° C. for 2 hours. LCMS showed the reaction wascompleted. The mixture was concentrated in vacuum to afford the titlecompound (207.00 mg, 527.56 mol, 99.83% yield, TFA) as yellow oil.

Step 7.(R*)—N-(5-chloro-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide*Pure but unknown diastereomer E1. To a mixture of8-(1-hydroxypropyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (50.00 mg, 127.43 μmol, 1.00eq, TFA) and phenyl N-(5-chloro-2,4-difluoro-phenyl)carbamate (46.99 mg,165.66 mol, 1.30 eq) in DCM (6.00 mL) was added TEA (128.95 mg, 1.27mmol, 176.64 μL, 10.00 eq) under N₂. The mixture was stirred at 25° C.for 10 hours. LCMS showed the reaction was completed. The residue waspoured into water (10 mL). The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC(FA) to afforded the title compound(40.00 mg, 84.89 μmol, 66.62% yield, 99.3% purity) as white solid. LCMS[M+1]: 468 ¹H NMR (400 MHz, CDCl₃) δ 8.17 (t, J=8.03 Hz, 1H), 6.94 (dd,J=8.47, 10.60 Hz, 1H), 6.59 (d, J=2.89 Hz, 1H), 4.70 (s, 2H), 4.40-4.42(n, 1H), 4.13-4.16 (m, 1H), 3.82-3.89 (m, 2H), 3.64-3.66 (m, 2H),3.46-3.48 (m, 1H), 3.19 (s, 3H), 2.85 (t, J=5.77 Hz, 2H), 2.46-2.47 (m,1H), 1.70-1.77 (m, 1H), 1.44-1.55 (m, 2H), 1.04 (t, J=7.40 Hz, 3H).

Compounds 096,097,098,099,100,101,102,103,104, and 105 were preparedfrom the corresponding enantiomer separately through an analogousmethod.

Compound 096_E2:(S*)—N-(5-chloro-2,4-difluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS [M+1]: 468 ¹H NMR (400 MHz, CDCl₃) δ 8.18 (t, J=8.03 Hz, 1H), 6.96(dd, J=8.47, 10.60 Hz, 1H), 6.61 (s, 1H), 4.71 (s, 2H), 4.40-4.42 (m,1H), 4.14-4.16 (m, 1H), 3.83-3.91 (m, 2H), 3.62-3.69 (m, 2H), 3.47-3.48(m, 1H), 3.20 (s, 3H), 2.86 (t, J=5.71 Hz, 2H), 2.47-2.49 (m, 1H),1.71-1.79 (m, 1H), 1.45-1.56 (m, 2H), 1.05 (t, J=7.34 Hz, 3H).

Compound 096_E3:(S*)—N-(5-chloro-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E3.

LCMS [M+1]: 468 ¹H NMR (400 MHz, CDCl₃) δ 8.18 (t, J=8.07 Hz, 1H), 6.96(dd, J=8.50, 10.45 Hz, 1H), 6.63 (br d, J=2.69 Hz, 1H), 4.59-4.77 (m,3H), 4.32 (m, 1H), 3.79-3.95 (m, 2H), 3.49-3.56 (m, 1H), 3.36-3.37 (m,2H), 3.20 (s, 3H), 2.87 (t, J=5.81 Hz, 2H), 2.46-2.54 (m, 1H), 1.90-2.20(m, 1H), 1.44-1.54 (m, 2H), 1.03 (t, J=7.40 Hz, 3H).

Compound 096_E4:(R*)—N-(5-chloro-2,4-difluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E4.

LCMS [M+1]: 468 ¹H NMR (400 MHz, CDCl₃) δ 8.18 (t, J=8.07 Hz, 1H), 6.96(dd, J=8.50, 10.58 Hz, 1H), 6.63 (s, 1H), 4.59-4.77 (m, 3H), 4.32 (m,1H), 3.79-3.95 (m, 2H), 3.50-3.56 (m, 1H), 3.36 (m, 2H), 3.20 (s, 3H),2.87 (t, J=5.81 Hz, 2H), 2.46-2.54 (m, 1H), 2.03 (s, 1H), 1.75 (br s,1H), 1.66 (m, 19H), 1.42-1.55 (m, 2H), 1.03 (t, J=7.34 Hz, 3H).

Compound 097_E1:(R*)—N-(3-cyano-4-fluorophenvl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS [M+1]: 441. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (dd, J=2.76, 5.52 Hz,1H), 7.60-7.63 (m, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.99-7.04 (m, 1H),4.64-4.75 (m, 2H), 4.43 (m, 1H), 4.15 (m, 1H), 3.81-3.95 (m, 2H), 3.66(m, 2H), 3.48 (m, 1H), 3.21 (s, 3H), 2.85 (t, J=5.71 Hz, 2H), 2.45-2.53(m, 1H), 1.79 (m, 1H), 1.44-1.59 (m, 2H), 1.05 (t, J=7.40 Hz, 3H).

Compound 097_E2:(S*)—N-(3-cyano-4-fluorophenvl)-8-((R*)-1-hydroxypropyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS [M+1]: 441. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (dd, J=2.76, 5.40 Hz,1H), 7.60-7.63 (m, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.99 (br s, 1H),4.64-4.75 (m, 2H), 4.43 (dd, J=7.28, 14.18 Hz, 1H), 4.15 (m, 1H),3.81-3.95 (m, 2H), 3.66 (m, 2H), 3.48 (m, 14.87 Hz, 1H), 3.21 (s, 3H),2.85 (t, J=5.83 Hz, 2H), 2.49 (m, 1H), 1.79 (br s, 1H), 1.60-1.71 (m,18H), 1.52 (m, 2H), 1.05 (t, J=7.40 Hz, 3H).

Compound 097_E3:(S*)—N-(3-cyano-4-fluorophenvl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E3.

LCMS [M+1]: 441. 1H NMR (400 MHz, CDCl₃) δ 7.79 (dd, J=2.69, 5.38 Hz,1H), 7.60-7.63 (m, 1H), 7.14 (t, J=8.68 Hz, 1H), 7.04 (s, 1H), 4.70-4.79(m, 1H), 4.59-4.69 (m, 2H), 4.33 (m, 1H), 3.81-3.95 (m, 2H), 3.50-3.58(m, 1H), 3.38 (m, 2H), 3.20 (s, 3H), 2.85 (t, J=5.81 Hz, 2H), 2.51 (m,1H), 1.97-2.18 (m, 1H), 1.46-1.57 (m, 1H), 1.45-1.56 (m, 1H), 1.04 (t,J=7.40 Hz, 3H).

Compound 097_E4:(R*)—N-(3-cyano-4-fluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.*Pure but unknowndiastereomer E4

LCMS [M+1]: 441. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (dd, J=2.75, 5.44 Hz,1H), 7.61-7.63 (m, 1H), 7.05-7.17 (m, 2H), 4.71-4.79 (m, 1H), 4.58-4.67(m, 2H), 4.33 (m, 1H), 3.81-3.95 (m, 2H), 3.51-3.57 (m, 1H), 3.38 (d,J=7.46 Hz, 2H), 3.20 (s, 3H), 2.85 (t, J=5.81 Hz, 2H), 2.47-2.55 (m,1H), 2.03 (s, 1H), 1.62-1.74 (m, 1H), 1.45-1.58 (m, 2H), 1.04 (t, J=7.40Hz, 3H).

Compound 098_E1:(R*)—N-(3-cyano-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS [M+1]: 459. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (dt, J=5.84, 9.13 Hz,1H), 7.01 (ddd, J=1.76, 7.97, 9.47 Hz, 1H), 6.73 (d, J=2.26 Hz, 1H),4.72 (d, J=3.51 Hz, 2H), 4.41 (m, 1H), 4.14 (m, 1H), 3.78-3.95 (m, 2H),3.59-3.71 (m, 2H), 3.46 (m, 1H), 3.19 (s, 3H), 2.85 (t, J=5.71 Hz, 2H),2.40-2.54 (m, 1H), 1.43-1.59 (m, 2H), 1.03 (t, J=7.40 Hz, 3H).

Compound 098_E2:(S*)—N-(3-cyano-2,4-difluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS [M+1]: 459 ¹H NMR (400 MHz, CDCl₃) δ 8.25 (dt, J=5.90, 9.10 Hz,1H), 7.01 (ddd, J=1.69, 7.94, 9.44 Hz, 1H), 6.73 (d, J=2.01 Hz, 1H),4.72 (d, J=3.64 Hz, 2H), 4.41 (m, 1H), 4.14 (m, 1H), 3.86 (m, 2H),3.57-3.71 (m, 2H), 3.46 (m, 1H), 3.19 (s, 3H), 2.85 (t, J=5.71 Hz, 2H),2.37-2.57 (m, 1H), 1.51 (dt, J=7.40, 14.93 Hz, 2H), 1.04 (t, J=7.40 Hz,3H).

Compound 098_E3:(S*)—N-(3-cyano-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E3.

LCMS [M+1]: 459. ¹H NMR (400 MHz, CDCl₃) δ 8.26 (dt, J=5.83, 9.13 Hz,1H), 7.01 (ddd, J=1.76, 7.97, 9.47 Hz, 1H), 6.72 (d, J=2.26 Hz, 1H),4.53-4.85 (m, 3H), 4.31 (m, 1H), 3.77-3.95 (m, 2H), 3.52 (m, 1H), 3.36(m, 2H), 3.19 (s, 3H), 2.86 (t, J=5.77 Hz, 2H), 2.42-2.56 (m, 1H),1.44-1.58 (m, 2H), 1.02 (t, J=7.40 Hz, 3H).

Compound 098_E4:(R*)—N-(3-cyano-2,4-difluorophenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E4.

LCMS [M+1]: 459. ¹H NMR (400 MHz, CDCl₃) δ 8.18-8.35 (m, 1H), 7.02 (ddd,J=1.76, 8.03, 9.54 Hz, 1H), 6.65-6.80 (m, 1H), 4.54-4.83 (m, 3H),4.20-4.37 (m, 1H), 3.75-3.96 (m, 2H), 3.47-3.59 (m, 1H), 3.36 (m, 2H),3.19 (s, 3H), 2.86 (s, 2H), 2.41-2.58 (m, 1H), 1.42-1.56 (m, 2H), 1.02(t, J=7.40 Hz, 3H).

Compound 099_E1:(R*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS [M+1]: 484. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J=2.63, 6.05 Hz,1H), 7.59 (td, J=3.38, 9.02 Hz, 1H), 7.12 (t, J=9.35 Hz, 1H), 6.87 (s,1H), 4.60-4.77 (m, 2H), 4.41 (m, 1H), 4.13 (m, 1H), 3.78-3.96 (m, 2H),3.64 (m, 2H), 3.47 (m, 1H), 3.19 (s, 3H), 2.84 (t, J=5.93 Hz, 2H),2.40-2.53 (m, 1H), 1.72-1.82 (m, 1H), 1.46-1.57 (m, 2H), 1.04 (t, J=7.40Hz, 3H).

Compound 099_E2:(S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS [M+1]: 484. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J=2.75, 6.17 Hz,1H), 7.56-7.63 (m, 1H), 7.12 (t, J=9.35 Hz, 1H), 6.87 (s, 1H), 4.61-4.78(m, 2H), 4.41 (m, 1H), 4.13 (m, 1H), 3.79-3.96 (m, 2H), 3.59-3.71 (m,2H), 3.47 (m, 1H), 3.19 (s, 3H), 2.84 (t, J=5.93 Hz, 2H), 2.38-2.54 (m,1H), 1.74 (br dd, J=3.24, 7.27 Hz, 1H), 1.71-1.81 (m, 1H), 1.51 (dt,J=7.64, 14.95 Hz, 2H), 1.04 (t, J=7.34 Hz, 3H).

Compound 099_E3:(S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E3.

LCMS [M+1]: 484. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J=2.57, 5.87 Hz,1H), 7.55-7.62 (m, 1H), 7.12 (t, J=9.41 Hz, 1H), 6.86 (s, 1H), 4.55-4.80(m, 3H), 4.31 (m, 14.37 Hz, 1H), 3.82-3.93 (m, 2H), 3.48-3.57 (m, 1H),3.36 (m, 2H), 3.19 (s, 3H), 2.84 (t, J=5.75 Hz, 2H), 2.39-2.54 (m, 1H),1.95-2.10 (m, 1H), 1.45-1.55 (m, 2H), 1.02 (t, J=7.40 Hz, 3H).

Compound 099_E4:(R*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E4.

LCMS [M+1]: 484. ¹H NMR (400 MHz, CDCl₃) δ 7.66-7.72 (m, 1H), 7.55-7.63(m, 1H), 7.12 (s, 1H), 6.86 (s, 1H), 4.55-4.79 (m, 3H), 4.24-4.37 (m,1H), 3.87 (s, 2H), 3.47-3.59 (m, 1H), 3.36 (d, J=7.46 Hz, 2H), 3.19 (s,3H), 2.80-2.89 (m, 2H), 2.44-2.55 (m, 1H), 1.99-2.13 (m, 1H), 1.44-1.55(m, 2H), 1.02 (t, J=7.40 Hz, 3H).

Compound 100_E1:(R*)—N-(3-chloro-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS [M+1]: 468 ¹H NMR (400 MHz, CDCl₃) δ 7.86 (dt, J=5.56, 8.89 Hz,1H), 6.90-7.00 (m, 1H), 6.60 (br s, 1H), 4.71 (d, J=1.34 Hz, 2H), 4.41(m, 1H), 4.13 (m, 1H), 3.80-3.92 (m, 2H), 3.56-3.70 (m, 2H), 3.46 (m,1H), 3.19 (s, 3H), 2.85 (t, J=5.62 Hz, 2H), 2.40-2.52 (m, 1H), 1.44-1.57(m, 2H), 1.04 (t, J=7.40 Hz, 3H).

Compound 101_E1:(R*)—N-(3-bromo-2,4-difluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS [M+1]: 512. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (dt, J=5.62, 8.93 Hz,1H), 6.93 (dt, J=2.08, 8.62 Hz, 1H), 6.61 (br s, 1H), 4.67-4.76 (m, 2H),4.41 (m, 1H), 4.13 (m, 1H), 3.80-3.89 (m, 1H), 3.58-3.70 (m, 2H), 3.46(m, 1H), 3.19 (s, 3H), 2.85 (t, J=5.81 Hz, 2H), 2.46 (m, 1H), 1.44-1.57(m, 2H), 1.03 (t, J=7.40 Hz, 3H).

Compound 102_E1:(R*)—N-(3-bromo-4-fluorophenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS [M+1]: 494. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (dd, J=2.69, 6.11 Hz,1H), 7.24-7.27 (m, 1H), 7.03 (t, J=8.56 Hz, 1H), 6.68 (s, 1H), 4.60-4.73(m, 2H), 4.41 (m, 1H), 4.13 (m, 1H), 3.76-3.93 (m, 2H), 3.64 (m, 2H),3.46 (m, 1H), 3.19 (s, 3H), 2.83 (t, J=5.75 Hz, 2H), 2.41-2.52 (m, 1H),1.76 (m, 1H), 1.43-1.57 (m, 2H), 1.04 (t, J=7.40 Hz, 3H).

Compound 103_E1:(R*)—N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS [M+1]: 502. ¹H NMR (400 MHz, CDCl₃) δ 8.13-8.28 (m, 1H), 6.90-7.10(m, 1H), 6.69 (br s, 1H), 4.63-4.80 (m, 2H), 4.05-4.47 (m, 2H), 3.86 (m,2H), 3.64 (m, 2H), 3.39-3.50 (m, 1H), 3.19 (s, 3H), 2.85 (br t, J=5.50Hz, 2H), 2.40-2.52 (m, 1H), 1.44-1.55 (m, 2H), 1.04 (t, J=7.40 Hz, 3H).

Compound 104_E1:(R*)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-N-(3,4,5-trifluorophenyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS [M+1]: 452. ¹H NMR (400 MHz, CDCl₃) δ 7.14 (dd, J=6.09, 9.60 Hz,2H), 6.74-6.86 (m, 1H), 4.58-4.73 (m, 2H), 4.41 (m, 1H), 4.13 (m, 1H),3.76-3.93 (m, 2H), 3.64 (m, 2H), 3.46 (m, 1H), 3.19 (s, 3H), 2.83 (br t,J=5.65 Hz, 2H), 2.40-2.53 (m, 1H), 1.41-1.57 (m, 2H), 1.04 (t, J=7.40Hz, 3H).

Compound 105_E1:(R*)-8-((S*)-1-hydroxypropyl)-10-methyl-11-oxo-N-(2,3,4,5-tetrafluorophenyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS [M+1]: 470. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (m, 1H), 6.71 (br s,1H), 4.70 (d, J=2.57 Hz, 2H), 4.41 (m, 1H), 4.13 (m, 1H), 3.78-3.92 (m,2H), 3.60-3.67 (m, 2H), 3.46 (m, 1H), 3.19 (s, 3H), 2.85 (t, J=5.75 Hz,2H), 2.40-2.52 (m, 1H), 1.42-1.57 (m, 2H), 1.03 (t, J=7.40 Hz, 3H).

Compound 106:N-(3-chloro-4-fluoro-phenyl)-8-(1-hydroxybutyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-butanoyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a mixture of propylmagnesium bromide (2 M, 490.85 μL, 2.00 eq) in THF(3.00 mL) was added tert-butyl8-[methoxy(methyl)carbamoyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Compound 096, Product from Step 2, 200.00 mg, 490.85 μmol, 1.00 eq) inTHF (3.00 mL) drop-wise at −10° C. under N₂. The mixture was heated to0° C. and stirred for 1 hours. LCMS showed the starting material/Desiredproduct=1:2, then added bromo(propyl)magnesium (2 M, 1.23 mL, 5.00 eq)at 0° C. and stirred for 1 hours. TLC (Ethyl acetate) showed thereaction was completed and mainly the desired product was detected. Themixture was poured into 1N HCl (50 mL) and stirred for 2 min. Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum to afford the title compound(170.00 mg, 217.68 μmol, 44.35% yield, 50% purity) as yellow solid.LCMS[M+1]: 391.

Step 2. tert-butyl8-(1-hydroxybutyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate. To a mixture oftert-butyl8-butanoyl-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(170.00 mg, 435.36 μmol, 1.00 eq) in MeOH (5.00 mL) was added NaBH₄(32.94 mg, 870.72 μmol, 2.00 eq) in one portion at −10° C. under N₂. Themixture was stirred at −10° C. for 30 min, then heated to 25° C. andstirred for 1 hours. LCMS and TLC (Petroleum ether: Ethyl acetate=0:1)showed the reaction was completed. The mixture was poured into water (10mL) and stirred for 2 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-TLC (ethyl acetate) to afford the titlecompound (75.00 mg, 185.36 μmol, 42.58% yield, 97% purity) as yellowsolid. LCMS [M+1]: 393.

Step 3.8-(1-hydroxybutyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a mixture of tert-butyl8-(1-hydroxybutyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(75.00 mg, 191.09 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g,13.51 mmol, 1.00 mL, 70.68 eq) in one portion at 30° C. under N₂. Themixture was stirred at 30° C. for 2 hours. TLC (Ethyl acetate) showedthe reaction was completed. The mixture was concentrated in vacuum toafford the title compound (77.66 mg, 191.09 μmol, 100.00% yield, TFA) asyellow oil.

Step 4.N-(3-chloro-4-fluoro-phenyl)-8-(1-hydroxybutyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a mixture of8-(1-hydroxybutyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (77.66 mg, 191.09 μmol, 1.00eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (50.77 mg,191.09 μmol, 1.00 eq) in DCM (6.00 mL) was added TEA (193.37 mg, 1.91mmol, 264.89 μL, 10.00 eq) under N₂. The mixture was stirred at 25° C.for 10 hours. LCMS showed the reaction was completed. The residue waspoured into water (10 mL) and stirred for 2 min. The aqueous phase wasextracted with ethyl acetate (10 mL*2). The combined organic phase waswashed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by prep-HPLC(FA) toafford the title compound (49.00 mg, 105.62 μmol, 55.27% yield) as whitesolid.

LCMS [M+1]: 464. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (dd, J=2.32, 6.36 Hz,1H), 7.22 (m, 1H), 7.01-7.11 (m, 1H), 6.73 (m, 1H), 4.54-4.78 (m, 3H),4.27-4.48 (m, 1H), 4.26-4.50 (m, 1H), 4.09-4.22 (m, 1H), 3.81-3.95 (m,2H), 3.58-3.79 (m, 2H), 3.43-3.51 (m, 1H), 3.35-3.42 (m, 1H), 3.20 (s,3H), 2.85 (br t, J=5.01 Hz, 2H), 2.41-2.53 (m, 1H), 1.40-1.55 (m, 4H),0.99 (q, J=7.05 Hz, 3H).

Compound 107_D1:(3R,8S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer D1.

To a solution of(3R,8S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Compound 122_D1, 45.00mg, 90.82 μmol, 1.00 eq) in MeOH (5.00 mL) was added Pd/C (5.00 mg, 10%purity) under N₂, the suspension was degassed under vacuum and purgedwith H₂ three times, the mixture was stirred under H₂ (15 psi) at 20° C.for 30 minutes. LCMS showed one main peak with desired MS was detected.The reaction mixture was filtered and the filtrate was concentrated. Theresidue was purified by prep-HPLC(FA) to afford the title compound(44.00 mg, 86.68 μmol, 95.44% yield, 98% purity) as white solid. LCMS(M+1): 498. ¹H NMR (400 MHz, CDCl₃) δ=7.69 (dd, J=2.75, 6.05 Hz, 1H),7.55-7.62 (m, 1H), 7.13 (t, J=9.41 Hz, 1H), 6.64 (s, 1H), 5.15 (m, 1H),4.80 (m, 1H), 4.39-4.54 (m, 2H), 4.12 (m, 1H), 3.62-3.71 (m, 2H), 3.48(m, 1H), 3.20 (s, 3H), 3.01 (m, 1H), 2.67 (m, 1H), 2.41-2.52 (m, 1H),1.45-1.57 (m, 2H), 1.19 (d, J=6.97 Hz, 3H), 1.05 (t, J=7.40 Hz, 3H).

Compounds 107109_D1&D2 were prepared in a manner analogous to Compound107.

Compound 107_D2:(3R,8R*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound107_D1, using Compound 122_D2.

*Pure but unknown diastereomer D2.

LCMS (M+1): 498. ¹H NMR (400 MHz, CDCl₃) δ=7.70 (dd, J=2.75, 6.17 Hz,1H), 7.55-7.62 (m, 1H), 7.13 (t, J=9.35 Hz, 1H), 6.66 (s, 1H), 5.16 (brt, J=6.36 Hz, 1H), 4.84 (m, 1H), 4.39-4.49 (m, 2H), 4.16 (m, 1H), 3.65(m, 2H), 3.48 (m, 1H), 3.20 (s, 3H), 3.03 (m, 1H), 2.65 (m, 1H),2.45-2.55 (m, 1H), 1.44-1.56 (m, 2H), 1.18 (d, J=6.85 Hz, 3H), 1.04 (t,J=7.40 Hz, 3H).

Compound 108_D1:(3R,8S*)—N-(3-cyano-4-fluorophenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound107_D1, using Compound 123_D1. *Pure but unknown diastereomer D1.

LCMS (M+1): 455. ¹H NMR (400 MHz, CDCl₃) δ=7.79 (dd, J=2.81, 5.38 Hz,1H), 7.59 (m, 1H), 7.13 (t, J=8.74 Hz, 1H), 6.80 (s, 1H), 5.14 (m, 1H),4.80 (m, 1H), 4.39-4.52 (m, 2H), 4.13 (m, 1H), 3.61-3.70 (m, 2H), 3.48(m, 1H), 3.20 (s, 3H), 3.01 (dd, J=5.81, 15.83 Hz, 1 H), 2.67 (m, 1H),2.43-2.53 (m, 1H), 1.44-1.60 (m, 2H), 1.19 (d, J=6.97 Hz, 3H), 1.04 (t,J=7.40 Hz, 3H).

Compound 108_D2:(3R,8R*)—N-(3-cyano-4-fluorophenvl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound107_D1, using Compound 123_D2. *Pure but unknown diastereomer D2.

LCMS (M+1): 455. ¹H NMR (400 MHz, CDCl₃) δ=7.80 (dd, J=2.81, 5.50 Hz,1H), 7.59 (m, 1H), 7.13 (t, J=8.74 Hz, 1H), 6.82 (s, 1H), 5.09-5.20 (m,1H), 4.84 (m, 1H), 4.39-4.48 (m, 2H), 4.15 (m, 1H), 3.65 (m, 2H), 3.48(m, 1H), 3.20 (s, 3H), 3.02 (m, 1H), 2.65 (m, 1H), 2.45-2.55 (m, 1H),1.43-1.60 (m, 2H), 1.18 (d, J=6.85 Hz, 3H), 1.04 (t, J=7.40 Hz, 3H).

Compound 109_D1:(3R,8S*)—N-(3-bromo-4-fluorophenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound107_D1, Compound 124_D1. *Pure but unknown diastereomer D1.

LCMS (M+1): 508/510. H NMR (400 MHz, CDCl₃) δ=7.74 (dd, J=2.70, 6.09 Hz,1H), 7.22-7.27 (m, 1H), 7.00-7.07 ((m, 1H), 6.55 (s, 1H), 5.08-5.19 ((m,1H), 4.78 (m, 1H), 4.39-4.51 (m, 2H), 4.11 (m, 1H), 3.61-3.71 (m, 2H),3.48 (m, 1H), 3.20 (s, 3H), 3.01 (m, 1H), 2.66 (m, 1H), 2.41-2.52 (m,1H), 1.42-1.57 (m, 2H), 1.18 (d, J=6.90 Hz, 3H), 1.05 (t, J=7.40 Hz,3H).

Compound 109_D2:(3R,8R*)—N-(3-bromo-4-fluorophenyl)-8-((R)-1-hydroxypropyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound107_D1, Compound 124_D2. *Pure but unknown diastereomer D2.

LCMS (M+1): 508/510. ¹H NMR (400 MHz, CDCl₃) δ=7.75 (dd, J=2.70, 6.09Hz, 1H), 7.25 (m, 1H), 7.04 (t, J=8.53 Hz, 1H), 6.61 (s, 1H), 5.15 (m,1H), 4.82 (d, J=15.43 Hz, 1H), 4.38-4.48 (m, 2H), 4.15 (m, 1H), 3.64 (m,2H), 3.47 (m, 1H), 3.19 (s, 3H), 3.02 (m, 1H), 2.64 (m, 1H), 2.45-2.55(m, 1H), 1.44-1.59 (m, 2H), 1.17 (d, J=6.90 Hz, 3H), 1.04 (t, J=7.40 Hz,3H).

Compound 110:N-(3-chloro-4-fluorophenyl)-11-methyl-12-oxo-3,4,7,8,9,10,11,12-octahydropyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazocine-2(1H)-carboxamide

Step 1.11-methyl-1,2,3,4,7,8,9,10-octahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazocin-12-one.To a solution of tert-butyl11-methyl-2-oxo-3,4,7,8,9,10-hexahydro-H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazocine-2-carboxylate(Intermediate 23, 61.00 mg, 182.41 μmol, 1.00 eq) in DCM (5.00 mL) wasadded TFA (308.00 mg, 2.70 mmol, 200.00 μL, 14.81 eq), then the mixturewas stirring at 25° C. for 1 h. TLC (PE: EtOAc=1:3) showed that compound7 consumed completely and one new spot formed. The mixture wasconcentrated in vacuo to afford the title compound (65.00 mg, crude,TFA) as yellow oil, without further purification and directly used inthe next step.

Step 2.N-(3-chloro-4-fluorophenvl)-11-methyl-12-oxo-3,4,7,8,9,10,11,12-octahydropyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazocine-2(1H)-carboxamide. To a solution of11-methyl-1,2,3,4,7,8,9,10-octahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazocin-12-one(65.00 mg, 186.61 mol, 1.00 eq, TFA) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (54.53 mg, 205.27 μmol, 1.10 eq)in DCM (3.00 mL) was added TEA (151.06 mg, 1.49 mmol, 206.94 μL, 8.00eq), then the mixture was stirring at 25° C. for 16 h. LCMS indicatedthat11-methyl-1,2,3,4,7,8,9,10-octahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazocin-12-onewas consumed completely and desired product was detected. The mixturewas concentrated in vacuo. The residue was purified by prep-HPLC (FA) toafford the title compound (33.32 mg, 81.61 μmol, 43.73% yield, 99.4%purity) as a yellow solid. LCMS: 406[M+1]. H NMR (400 MHz, CDCl₃) δ=7.58(dd, J=2.69, 6.60 Hz, 1H), 7.16-7.22 (m, 1H), 7.02-7.09 (m, 1H), 6.55(s, 1H), 4.60 (s, 2H), 4.29 (br s, 2H), 3.85 (t, J=5.75 Hz, 2H), 3.31(br d, J=8.80 Hz, 2H), 3.14 (s, 3H), 2.84 (t, J=5.81 Hz, 2H), 1.97 (brs, 2H), 1.86 (br s, 2H).

Compound 111:(Z)—N-(3-chloro-4-fluorophenvl)-11-methyl-12-oxo-3,4,7,10,11,12-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazocine-2(1H)-carboxamide

Step 1. (8Z)-11-methyl-1,2,3,4,7,10-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazocin-12-one. To a solution of tert-butyl(8Z)-11-methyl-12-oxo-3,4,7,10-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazocine-2-carboxylate(Intermediate 22, 50.00 mg, 150.42 μmol, 1.00 eq) in DCM (3.00 mL) wasadded TFA (329.99 mg, 2.89 mmol, 214.28 μL, 19.24 eq), then the mixturewas stirring at 25° C. for 1 h. TLC (PE: EtOAc=1:3) showed that thereactant 6 consumed completely and one new spot formed. The mixture wasconcentrated in vacuum. The title compound (55.00 mg, crude, TFA) wasobtained as yellow oil.

Step 2. (Z)—N-(3-chloro-4-fluorophenvl)-11-methyl-12-oxo-3,4,7,10,11,12-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazocine-2(1H)-carboxamide. To a solution of(8Z)-11-methyl-1,2,3,4,7,10-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazocin-12-one (55.00 mg, 158.82 mol, 1.00 eq, TFA) andphenyl N-(3-chloro-4-fluoro-phenyl)carbamate (46.41 mg, 174.70 μmol,1.10 eq) in DCM (3.00 mL) was added TEA (128.57 mg, 1.27 mmol, 176.12μL, 8.00 eq), then the mixture was stirring at 25° C. for 16 h. LCMSindicated that (8Z)-11-methyl-1,2,3,4,7,10-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazocin-12-one was consumed completely anddesired product was detected. The mixture was concentrated in vacuo. Theresidue was purified by prep-HPLC(FA) to afford the title compound(25.57 mg, 62.68 μmol, 39.47% yield, 99% purity) as yellow solid. LCMS:404[M+1]. ¹H NMR (400 MHz, CDCl₃) δ=7.57 (dd, J=2.63, 6.54 Hz, 1H),7.16-7.21 (m, 1H), 7.03-7.09 (m, 1H), 6.54 (s, 1H), 5.91-6.05 (m, 2H),4.89 (d, J=3.79 Hz, 2H), 4.61 (s, 2H), 3.85 (t, J=5.87 Hz, 2H), 3.80 (brd, J=5.38 Hz, 2H), 3.12 (s, 3H), 2.85 (t, J=5.81 Hz, 2H).

Compound 112:N-(3-cyano-4-fluorophenvl)-7-(3,3-difluoro-1-hydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 116,using phenyl (3-cyano-4-fluorophenyl)carbamate in Step 5. LCMS:477[M+1]. ¹H NMR (400 MHz, CDCl₃) δ=7.79 (dd, J=2.7, 5.4 Hz, 1H), 7.60(br d, J=9.8 Hz, 1H), 7.15 (t, J=8.6 Hz, 1H), 6.79 (brs, 1H), 5.92-6.28(m, 1H), 4.58-4.80 (m, 3H), 4.22-4.49 (m, 2H), 4.13 (brs, 1H), 3.84-3.95(m, 3H), 3.63 (m, 1H), 3.29-3.50 (m, 2H), 3.21 (d, J=2.6 Hz, 3H), 2.86(br t, J=5.5 Hz, 2H), 2.70 (brs, 1H), 2.56 (brd, J=6.2 Hz, 1H), 2.25(brs, 1H), 2.00-2.13 (m, 2H).

Compound 113:2-((3-chloro-4-fluorophenvl)carbamoyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylic Acid

Step 1. methyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylate and2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylic acid. To a solution of2-(tert-butoxycarbonyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylic acid (Intermediate 26,116.00 mg) in MeOH (2.00 mL) was added HCl/MeOH (4 M, 2.00 mL). Themixture was stirred at 20° C. for 2 hr. TLC (DCM:MeOH=10:1) showed onemain spot appeared. The mixture was concentrated in vacuum a residue(96.00 mg, crude, HCl) as brown oil.

Step 2.2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3.4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylic acid. To a solution ofmethyl above oil (95.00 mg, 301.81 mol, 1.00 eq, HCl) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (80.18 mg, 301.81 mol, 1.00 eq) inDCM (3.00 mL) was added TEA (152.70 mg, 1.51 mmol, 209.18 μL, 5.00 eq).The mixture was stirred at 20° C. for 5 hr. Several peaks showed onLCMS, 24%2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylic acid and 22% methyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylate were detected. Themixture was extracted with EtOAc (10 mL*2) and H₂O (10 mL). The combinedorganic layer was washed 1N HCl (10 mL), dried over Na₂SO₄, filtratedand concentrated in vacuum. The residue was purified by prep-TLC(PE:EtOAc=0:1) and prep-HPLC(FA) to afford methyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylate (40.00 mg, 88.92 μmol,29.46% yield) as colorless oil and2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylic acid (9.00 mg, 19.25μmol, 6.38% yield, 93.2% purity) as white solid. LCMS: 436[M+1]. ¹H NMR(400 MHz, METHANOL-d₄) 6=7.61 (dd, J=2.63, 6.66 Hz, 1H), 7.26-7.38 (m,1H), 7.06-7.20 (m, 1H), 5.32 (br d, J=9.54 Hz, 1H), 4.65-4.73 (m, 1H),4.54-4.80 (m, 1H), 4.69 (brs, 3H), 3.71-3.97 (m, 2H), 3.54-3.65 (m, 1H),3.52-3.65 (m, 1H), 3.37-3.52 (m, 1H), 3.36-3.52 (m, 1H), 3.66 (s, 1H),3.36-3.53 (m, 1H), 3.34-3.70 (m, 1H), 3.15 (brs, 1H), 3.08 (s, 2H),2.98-3.00 (m, 1H), 2.90-2.99 (m, 1H), 2.89-2.99 (m, 1H), 2.89-2.99 (m,1H), 2.89-2.99 (m, 1H), 2.88-3.00 (m, 1H), 2.74-2.86 (m, 2H), 2.41-2.60(m, 1H), 2.41-2.60 (m, 1H).

Compound 114:N-(3-chloro-4-fluorophenyl)-7-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. methyl10-methyl-11-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-7-carboxylate.To a solution of2-(tert-butoxycarbonyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylic acid (Intermediate 26,370.00 mg, 1.02 mmol, 1.00 eq) in MeOH (10.00 mL) was added HCl/MeOH (4M, 10.00 mL, 39.22 eq). The mixture was heated to 45° C. for 1 hr. TLC(DCM:MeOH=10:1) showed the starting material consumed and one main spotappeared. The mixture was concentrated in vacuum to afford methyl10-methyl-1-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-7-carboxylate(340.00 mg, crude, HCl) as brown solid.

Step 2. 2-tert-butyl 7-methyl 10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,7-dicarboxylate. To asolution of methyl 10-methyl-1-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyra-zolo[2,4-c][1,4]diazepine-7-carboxylate (240.00 mg, 762.46μmol, 1.00 eq, HCl) in DCM (10.00 mL) was added TEA (385.77 mg, 3.81mmol, 528.45 μL, 5.00 eq) followed by Boc₂O (332.81 mg, 1.52 mmol,350.33 μL, 2.00 eq). The mixture was heated to 20° C. for 16 hr. LCMSshowed one main peak with desired Ms detected. The mixture was extractedwith EtOAc (20 mL*3) and H₂O (10 mL). The combined organic layer waswashed with 1N HCl (10 mL), dried over Na₂SO₄, filtrated andconcentrated in vacuum. The residue was purified by columnchromatography (PE:EtOAc=70%˜100%) to afford the title compound (160.00mg, 422.81 μmol, 55.45% yield) as colorless oil.

Step 3. tert-butyl7-(hydroxymethyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2-carboxylate.To a solution of 2-tert-butyl 7-methyl10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2,7-dicarboxylate (60.00 mg,158.55 μmol, 1.00 eq) in THF (3.00 mL) was added LiBH₄ (13.81 mg, 634.20μmol, 4.00 eq) at 0° C. The mixture was stirred at 25° C. for 1 hr. TLC(PE:EtOAc=0:1) showed the starting material consumed and three new spotsformed. LCMS showed one main peak with desired Ms detected. The mixturewas quenched with saturated NH₄Cl (20 mL) and extracted with EtOAc (20mL*3). The combined organic layer was dried over Na₂SO₄, filtrated andconcentrated in vacuum to afford the title compound (45.00 mg, crude) ascolorless oil.

Step 5.N-(3-chloro-4-fluorophenyl)-7-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. To a solution oftert-butyl7-(hydroxymethyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-c][1,4]diazepine-2-carboxylate(60.00 mg, 171.23 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (4.62 g,40.52 mmol, 3.00 mL, 236.64 eq). The mixture was stirred at 25° C. for 1hr. TLC (PE:EtOAc=0:1) showed the starting material consumed. Themixture was concentrated in vacuum to get7-(hydroxymethyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepin-11-one(63.00 mg, crude, TFA) as brown oil.

Step 6.N-(3-chloro-4-fluorophenyl)-7-(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. To a solution of7-(hydroxymethyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-c][1,4]diazepin-11-one (62.00 mg, 170.18 μmol, 1.00eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (45.21 mg,170.18 mol, 1.00 eq) in DCM (3.00 mL) was added TEA (86.10 mg, 850.90μmol, 117.95 μL, 5.00 eq). The mixture was stirred at 20° C. for 5 hr.TLC (DCM:MeOH=10:1) showed one main spot appeared. The mixture wasextracted with EtOAc (10 mL*2) and H₂O (10 mL). The combined organiclayer was washed 1N HCl (10 mL), dried over Na₂SO₄, filtrated andconcentrated in vacuum. The residue was purified by prep-TLC(DCM:MeOH=10:1) to get 40 mg product, which was combined with anotherbatch (EW619-1536, 15 mg with 80% purity) to further purify byprep-HPLC(FA) to afford the title compound (40.00 mg, 65.51 μmol, 38.50%yield, 98.7% purity) as colorless oil. LCMS: 422[M+1]. ¹H NMR (400 MHz,METHANOL-d₄) δ=7.60 (dd, J=2.57, 6.60 Hz, 1H), 7.27-7.35 (m, 1H),7.11-7.19 (m, 1H), 4.59-4.73 (m, 3H), 3.84-3.94 (m, 1H), 3.72-3.83 (m,3H), 3.53-3.63 (m, 1H), 3.36-3.46 (m, 1H), 3.15 (s, 3H), 2.83 (t, J=5.75Hz, 2H), 2.40-2.52 (m, 1H), 2.23-2.35 (m, 1H).

Compound 115:N-(3-chloro-4-fluoro-phenyl)-8-(3-fluoro-1-hydroxy-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-(1-benzyloxy-3-fluoro-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl8-(1-benzyloxy-3-hydroxy-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 28, 90.00 mg, 185.72 μmol, 1.00 eq) in THF (1.00 mL) wasadded DAST (119.75 mg, 742.88 μmol, 98.16 μL, 4.00 eq) at −40° C. Themixture was stirred at −40° C. for 1 hr. TLC (PE:EtOAc=1:2) showed thestarting material consumed and one main spot appeared. The mixture wasextracted with DCM (10 mL*2) and H₂O (10 mL). The combined organic layerwas washed saturated NaHCO₃ (10 mL), dried over Na₂SO₄, filtrated andconcentrated in vacuum. The residue was purified by prep-TLC(PE:EtOAc=1:2) to afford the title compound (55.00 mg, 91.56 μmol,49.30% yield, 81% purity) as yellow oil.

Step 2. tert-butyl8-(3-fluoro-1-hydroxy-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl8-(1-benzyloxy-3-fluoro-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(55.00 mg, 113.03 μmol, 1.00 eq) in MeOH (10.00 mL) was added Pd/C(50.00 mg) under N₂. The suspension was degassed under vacuum and purgedwith H₂ several times. The mixture was stirred under H₂ (50 Psi) at 30°C. for 32 hours. LCMS indicated that 70% of the starting material stillremained and 13% of desired product was detected. Then the mixture wasfiltered and the filtrate was added Pd/C (50.00 mg) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (50 Psi) at 30° C. for 48 hours. LCMSindicated that 8% of the starting material still remained and 70% ofdesired product was detected. The mixture was filtered and concentratedin vacuum. The title compound (45.00 mg, crude) was obtained ascolorless oil.

Step 3.8-(3-fluoro-1-hydroxy-propyl)-10-methyl-2,3A7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl8-(3-fluoro-1-hydroxy-propyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(45.00 mg, 113.50 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (308.00mg, 2.70 mmol, 200.00 μL, 23.80 eq) with stirring at 20° C. for 1 h. TLC(PE: EtOAc=0:1) showed that the reactant 9 consumed completely and onemain new spot formed. The mixture was concentrated in vacuum. The titlecompound (47.00 mg, crude, TFA) was obtained as yellow oil and used inthe next step.

Step 4.N-(3-chloro-4-fluoro-phenyl)-8-(3-fluoro-1-hydroxy-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a solution of8-(3-fluoro-1-hydroxy-propyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(47.00 mg, 114.53 mol, 1.00 eq, TFA) and TEA (69.54 mg, 687.18 μmol,95.26 μL, 6.00 eq) in DCM (2.00 mL) was added phenylN-(3-chloro-4-fluoro-phenyl)carbamate (30.43 mg, 114.53 mol, 1.00 eq)with stirring at 20° C. for 16 h. LCMS indicated that the startingmaterial was consumed completely and desired product was detected. Themixture was concentrated in vacuum. The resulting residue was purifiedby prep-HPLC (FA) to afford the title compound (10.00 mg, 21.16 μmol,18.47% yield, 99% purity) as white solid. LCMS: 468[M+1]. ¹H NMR (400MHz, CDCl₃) δ=7.59 (dd, J=2.64, 6.53 Hz, 1H), 7.15-7.22 (m, 1H),7.03-7.09 (m, 1H), 6.56 (s, 1H), 4.71-4.84 (m, 1H), 4.61-4.71 (m, 3H),4.39-4.61 (m, 1H), 4.15-4.39 (m, 1H), 3.99 (br s, 1H), 3.79-4.03 (m,3H), 3.30-3.68 (m, 2H), 3.19 (d, J=4.02 Hz, 3H), 2.84 (t, J=5.65 Hz,2H), 2.50-2.61 (m, 1H), 2.16-2.43 (m, 1H), 1.78-2.00 (m, 2H).

Compound 116:N-(3-chloro-4-fluoro-phenyl)-8-(3,3-difluoro-1-hydroxy-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-(1-benzyloxy-3-oxo-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl8-(1-benzyloxy-3-hydroxy-propyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 28, 200.00 mg, 412.72 μmol, 1.00 eq) in DCM (4.00 mL) wasadded Dess-Martin (525.15 mg, 1.24 mmol, 383.32 μL, 3.00 eq) at 0° C.The mixture was stirred at 25° C. for 1 hr. TLC (PE:EtOAc=0:1) showedthe starting material consumed and one main new spot formed. Thereaction mixture was diluted with DCM (50 mL) and filtrated. Thefiltrate was concentrated in vacuum. The residue was purified byprep-TLC (PE:EtOAc=0:1) to afford the title compound (160.00 mg, 331.56μmol, 80.34% yield) as white solid.

Step 2. tert-butyl8-(1-benzyloxy-3,3-difluoro-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate. To asolution of tert-butyl8-(1-benzyloxy-3-oxo-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(116.00 mg, 227.95 μmol, 1.00 eq) in DCM (1.00 mL) was added DAST(146.97 mg, 911.80 μmol, 120.47 μL, 4.00 eq) at −40° C. The mixture wasstirred at 20° C. for 1 hr. TLC (PE:EtOAc=1:1) showed the startingmaterial consumed and one main spot formed. The mixture was extractedwith DCM (10 mL*2) and H₂O (10 mL). The combined organic layer was driedover Na₂SO₄, filtrated and concentrated in vacuum. The residue waspurified by prep-TLC (PE:EtOAc=1:1) to get tert-butyl8-(1-benzyloxy-3,3-difluoro-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(75.00 mg, 123.37 μmol, 54.12% yield, 83% purity) as yellow oil. Theresidue was purified by prep-HPLC (FA) to afford the title compound(56.00 mg, 109.54 μmol, 69.09% yield, 98.7% purity) as yellow oil.

Step 3. tert-butyl8-(3,3-difluoro-1-hydroxy-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.To a solution of tert-butyl8-(1-benzyloxy-3,3-difluoro-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(50.00 mg, 99.09 mol, 1.00 eq) in MeOH (15.00 mL) was added Pd/C (10.00mg, 99.09 μmol, 10% purity, 1.00 eq) and HOAc (595.06 ug, 9.91 μmol,0.57 μL, 0.10 eq) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 25° C. for 24 hours. TLC (PE:EtOAc=0:1) showed the starting materialremained, the mixture was diluted with MeOH (20 mL), filtrated. Thefiltrate was added Pd/C (20 mg) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (40 psi) at 30° C. for 20 hours. LCMS showed the startingmaterial remained and 60% desired product. The mixture was stirred underH₂ (45 psi) at 30° C. for another 16 hours. LCMS showed the startingmaterial consumed completely. The mixture was diluted with MeOH (30 mL)and filtrated. The filtrate was concentrated in vacuum to afford thetitle compound (60.00 mg, crude) as yellow oil.

Step 4.8-(3,3-difluoro-1-hydroxy-propyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one. To a solution of tert-butyl8-(3,3-difluoro-1-hydroxy-propyl)-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(60.00 mg, 144.77 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (40.52mmol, 3.00 mL, 279.89 eq). The mixture was stirred at 20° C. for 0.5 hr.TLC (PE:EtOAc=0:1) showed the starting material consumed. The mixturewas concentrated in vacuum to afford the title compound (64.00 mg,crude, TFA) as yellow oil.

Step 5.N-(3-chloro-4-fluoro-phenyl)-8-(3,3-difluoro-1-hydroxy-propyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.To a solution of8-(3,3-difluoro-1-hydroxy-propyl)-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(30.00 mg, 70.04 μmol, 1.00 eq, TFA) and phenylN-(3-chloro-4-fluoro-phenyl)carbamate (18.61 mg, 70.04 mol, 1.00 eq) inDCM (5.00 mL) was added TEA (35.44 mg, 350.20 μmol, 48.55 μL, 5.00 eq).The mixture was stirred at 20° C. for 16 hr. LCMS showed one main peak(254 nm) with desired Ms detected. The mixture was concentrated invacuum. The residue was purified by prep-HPLC (FA) to afford the titlecompound (14.00 mg, 28.32 μmol, 40.44% yield, 98.3% purity) as whitesolid. LCMS: 486[M+1]. ¹H NMR (400 MHz, CDCl₃) δ=7.79 (dd, J=2.7, 5.4Hz, 1H), 7.60 (br d, J=9.8 Hz, 1H), 7.15 (t, J=8.6 Hz, 1H), 6.79 (brs,1H), 5.92-6.28 (m, 1H), 4.58-4.80 (m, 3H), 4.22-4.49 (m, 2H), 4.13 (brs,1H), 3.84-3.95 (m, 3H), 3.63 (m, 1H), 3.29-3.50 (m, 2H), 3.21 (d, J=2.6Hz, 3H), 2.86 (br t, J=5.5 Hz, 2H), 2.70 (brs, 1H), 2.56 (br d, J=6.2Hz, 1H), 2.25 (brs, 1H), 2.00-2.13 (m, 2H).

Compound 117:8-(acetamidomethyl)-N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

A mixture of8-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(Compound 070, 30.00 mg, 71.28 μmol, 1.00 eq), TEA (10.82 mg, 106.92mol, 14.82 μL, 1.50 eq) and Ac₂O (8.73 mg, 85.54 μmol, 8.01 μL, 1.20 eq)in DCM (3.00 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 20° C. for 1 hour under N2 atmosphere. LCMSshowed the starting material was consumed completely, desired productwas major. The mixture was poured into water (10 mL) and stirred at 5min. The aqueous phase was extracted with DCM (5 mL*3). The combinedorganic phase was washed with brine (10 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byPrep-HPLC (HCl) to afford the title compound (25.00 mg, 53.47 μmol,75.01% yield, 99% purity) as a white solid. LCMS: 463/465 [M+1]. ¹H NMR(400 MHz, CDCl₃) δ 7.55-7.61 (m, 1H), 7.15-7.22 (m, 1H), 7.04-7.10 (m,1H), 6.47 (s, 1H), 6.12-6.20 (m, 1H), 4.67 (m, 2H), 4.29-4.45 (m, 2H),3.87 (m, 2H), 3.41 (m, 2H), 3.19 (s, 4H), 3.01-3.13 (m, 1H), 2.88 (m,3H), 2.00 (s, 3H).

Compound 118:N-(3-cyano-4-fluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.8-[(2,2-difluoroethylamino)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.A solution oftert-butyl8-[(2,2-difluoroethylamino)methyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 29, 80.00 mg, 193.49 μmol, 1.00 eq) in DCM (2.00 mL) wasadded TFA (6.16 g, 54.03 mmol, 4.00 mL, 279.23 eq), and then the mixturewas stirred at 20° C. for 1 hour. TLC showed the starting material wasconsumed completely and a new spot formed. The mixture was concentratedin vacuum to afford the title compound (104.75 mg, 193.48 μmol, 100.00%yield, 2TFA) as a yellow oil, which was used directly for next step.

Step 2.N-(3-cyano-4-fluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of8-[(2,2-difluoroethylamino)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(80.00 mg, 147.77 μmol, 1.00 eq, 2TFA), phenylN-(3-cyano-4-fluoro-phenyl)carbamate (34.08 mg, 132.99 μmol, 0.90 eq),TEA (29.91 mg, 295.54 mol, 40.97 μL, 2.00 eq) in DCM (3.00 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 30° C. for 16 hour under N2 atmosphere. LCMS showed thestarting material was consumed completely, desired product was major.The mixture was poured into water (10 mL) and extracted with DCM (5 mL).The combined organic phase was washed with brine (10 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by Prep-HPLC (HCl), following by Prep-HPLC (BASE) to afford thetitle compound (51.00 mg, 106.19 μmol, 71.86% yield, 99% purity) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (dd, J=2.75, 5.44 Hz, 1H),7.55-7.62 (m, 1H), 7.09-7.16 (m, 1H), 6.79 (s, 1H), 5.70-5.98 (m, 1H),4.68 (s, 2H), 4.36-4.47 (m, 1H), 4.17 (dd, J=5.62, 14.31 Hz, 1H),3.80-3.92 (m, 2H), 3.42-3.50 (m, 1H), 3.30-3.40 (m, 1H), 3.18 (s, 3H),2.94-3.07 (m, 2H), 2.69-2.87 (m, 4H), 2.50-2.62 (m, 1H), 1.14-1.31 (m,1H).

Compound 118_E1:(R*)—N-(3-cyano-4-fluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

Step 1. tert-butyl8-[[tert-butoxycarbonyl(2,2-difluoroethyl)amino]methyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of racemic tert-butyl8-[(2,2-difluoroethylamino)methyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 29, 1.60 g, 3.87 mmol, 1.00 eq), Boc₂O (2.53 g, 11.61mmol, 2.67 mL, 3.00 eq), TEA (1.37 g, 13.54 mmol, 1.88 mL, 3.50 eq) inDCM (20.00 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 30° C. for 72 hour under N2 atmosphere. TLCshowed the starting material was consumed completely, and a new spotformed. The mixture was concentrated in vacuum. The residue was purifiedby column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to1:1) to afford the title compound (1.88 g, 3.51 mmol, 90.81% yield, 96%purity) as a yellow solid, which was separated by SFC (column: IC (250mm*30 mm, 10 um); mobile phase: [0.1% NH₃H₂O IPA]; B %: 40%-40%,4.7 min;500 minmin) to give each 930 mg of both enantiomers.

Step 2.8-[(2,2-difluoroethylamino)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl8-[[tert-butoxycarbonyl(2,2-difluoroethyl)amino]methyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(630.00 mg, 1.23 mmol, 1.00 eq) in DCM (4.00 mL) was added TFA (3.08 g,27.01 mmol, 2.00 mL, 21.96 eq) at 0° C. The mixture was stirred at 25°C. for 1 h. The mixture was concentrated under reduced pressure toafford the title compound (665.00 mg, 1.17 mmol, 94.87% yield, 95%purity, 2TFA) as yellow oil, the crude product was used directly for thenext step.

Step 3.(R*)—N-(3-cyano-4-fluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. To a solution of8-[(2,2-difluoroethylamino)methyl]-10-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(52.00 mg, 96.05 μmol, 1.00 eq, 2TFA) in DCM (3.00 mL) was added phenylN-(3-cyano-4-fluoro-phenyl)carbamate (24.61 mg, 96.05 μmol, 1.00 eq) andEt₃N (48.60 mg, 480.25 μmol, 66.57 μL, 5.00 eq). The mixture was stirredat 25° C. for 16 h. The mixture was concentrated under reduced pressure.The residue combined with EW5335-130 was purified by prep-HPLC(HCl) toafford the title compound (37.50 mg, 71.05 μmol, 97% purity, HCl) asyellow solid. LCMS:476 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.81 (dd,J=2.81, 5.62 Hz, 1H), 7.69 (m, 1H), 7.27 (t, J=8.99 Hz, 1H), 6.21-6.52(m, 1H), 4.69 (s, 2H), 4.52 (m, 1H), 4.33 (m, 1H), 3.73-3.94 (m, 2H),3.53-3.72 (m, 3H), 3.09-3.26 (m, 5H), 2.97 (br d, J=6.48 Hz, 1H),2.77-2.88 (m, 2H).

118/119/127-125_E1, 118/119/127-125_E2 were prepared through ananalogous procedure to Compound 118.

Compound 118_E2:(S*)—N-(3-cyano-4-fluorophenvl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound118_E1. *Pure but unknown diastereomer E2. LCMS:476 [M+1]. ¹H NMR (400MHz, CDCl₃) δ 7.77 (dd, J=2.76, 5.40 Hz, 1H), 7.61 (m, 1H), 7.12 (t,J=8.72 Hz, 1H), 7.06 (s, 1H), 5.65-6.01 (m, 1H), 4.61-4.74 (m, 2H), 4.40(m, 1H), 4.17 (m, 1H), 3.86 (t, J=5.83 Hz, 2H), 3.30-3.52 (m, 2 H), 3.17(s, 3H), 2.93-3.07 (m, 2H), 2.84 (t, J=5.77 Hz, 2H), 2.67-2.79 (m, 2H),2.50-2.61 (m, 1H).

Compound 119:8-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl8-[[2,2-difluoroethyl-(2,2,2-trifluoroacetyl)amino]methyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture oftert-butyl8-[(2,2-difluoroethylamino)methyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(Intermediate 29, 89.00 mg, 215.26 μmol, 1.00 eq), TEA (43.56 mg, 430.52μmol, 59.67 μL, 2.00 eq) in DCM (5.00 mL) was added(2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (67.82 mg, 322.89 μmol,44.91 μL, 1.50 eq) dropwise at 0° C. under N₂. Then the mixture wasstirred at 30° C. for 1 hour under N2 atmosphere. TLC showed thestarting material was consumed completely, desired product was major.The mixture was poured into water (10 mL) and extracted with DCM (5mL*3). The combined organic phase was washed with brine (10 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by Prep-TLC (DCM/MeOH=10/1) to afford the title compound(85.00 mg, 158.50 μmol, 73.63% yield, 95% purity) as a white solid.LCMS: 509 [M+1].

Step 2.N-(2,2-difluoroethyl)-2,2,2-trifluoro-N-[(10-methyl-11-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl)methyl]acetamide.A solution oftert-butyl8-[[2,2-difluoroethyl-(2,2,2-trifluoroacetyl)amino]methyl]-10-methyl-1-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(85.00 mg, 166.84 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (2.62 g,22.96 mmol, 1.70 mL, 137.62 eq), and then the mixture was stirred at 30°C. for 1 hour. TLC showed the starting material was consumed completely,a new spot appeared. The mixture was concentrated in vacuum to affordthe title compound (87.00 mg, 166.23 μmol, 99.63% yield, TFA) as ayellow oil, which was used directly for next step.

Step 3.8-[[2,2-difluoroethyl-(2,2,2-trifluoroacetyl)amino]methyl]-N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide.A mixture ofN-(2,2-difluoroethyl)-2,2,2-trifluoro-N-[(10-methyl-11-oxo-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-8-yl)methyl]acetamide(85.00 mg, 162.41 μmol, 1.00 eq, TFA), phenylN-[4-fluoro-3-(trifluoromethyl)phenyl] carbamate (58.31 mg, 194.89 μmol,1.20 eq), TEA (82.17 mg, 812.03 μmol, 112.56 μL, 5.00 eq) in DCM (5.00mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 30° C. for 16 hour under N2 atmosphere. LCMS showed thestarting material was consumed completely, desired product was major.The mixture was poured into water (10 mL) and stirred at 5 min. Theaqueous phase was extracted with DCM (5 mL*3). The combined organicphase was washed with brine (10 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byPrep-TLC (PE/EtOAc=0/1) to afford the title compound (74.00 mg, 115.61μmol, 71.19% yield, 96% purity) as a white solid. LCMS: 614 [M+1].

Step 4.8-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of8-[[2,2-difluoroethyl-(2,2,2-trifluoroacetyl)amino]methyl]-N-[4-fluoro-3-(trifluoromethyl)phenyl]-10-methyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide(74.00 mg, 120.43 μmol, 1.00 eq), K₂CO₃ (49.93 mg, 361.29 mol, 3.00 eq)in MeOH (5.00 mL) and H₂O (1.00 mL) was degassed and purged with N₂ for3 times, and then the mixture was stirred at 50° C. for 1 hour under N2atmosphere. LCMS showed the starting material was consumed completely,and desired product was major. The mixture was poured into water (10 mL)and extracted with DCM (5 mL*3). The combined organic phase was washedwith brine (10 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by Prep-HPLC (Base) toafford the title compound (32.00 mg, 59.25 μmol, 49.20% yield, 96%purity) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.66-7.71 (m, 1H),7.56-7.62 (m, 1H), 7.09-7.16 (m, 1H), 6.75-6.80 (m, 1H), 5.67-6.03 (m,1H), 4.69 (s, 2H), 4.35-4.47 (m, 1H), 4.12-4.23 (m, 1H), 3.87 (m, 2H),3.42-3.50 (m, 1H), 3.35-3.37 (d, J=7.28 Hz, 1H), 3.18 (s, 3H), 2.95-3.06(m, 2H), 2.68-2.88 (m, 4H), 2.50-2.62 (m, 1H), 1.11-1.34 (m, 1H).

Compound 119_E1:(R*)-8-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS: 519 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (dd, J=2.70, 6.09 Hz,1H), 7.55-7.63 (m, 1H), 7.12 (t, J=9.41 Hz, 1H), 6.87 (s, 1H), 5.67-6.01(m, 1H), 4.69 (d, J=1.51 Hz, 2H), 4.40 (dd, J=6.78, 14.31 Hz, 1H), 4.17(m, 1H), 3.81-3.92 (m, 2H), 3.30-3.50 (m, 2H), 3.12-3.22 (m, 3H),2.94-3.06 (m, 2H), 2.84 (t, J=5.77 Hz, 2H), 2.67-2.80 (m, 2H), 2.50-2.63(m, 1H).

Compound 119_E2:(S*)-8-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS: 519 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (dd, J=2.70, 6.09 Hz,1H), 7.54-7.63 (m, 1H), 7.12 (t, J=9.35 Hz, 1H), 6.78 (s, 1H), 5.66-6.02(m, 1H), 4.64-4.75 (m, 2H), 4.41 (m, 1H), 4.17 (m, 1H), 3.79-3.93 (m,2H), 3.29-3.50 (m, 2H), 3.18 (s, 3H), 3.01 (m, 2H), 2.84 (t, J=5.77 Hz,2H), 2.68-2.80 (m, 2H), 2.50-2.61 (m, 1H).

Compound 120:N-(3-cyano-4-fluorophenyl)-10-methyl-11-oxo-8-(((2,2,2-trifluoroethyl)amino)methyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-butyl10-methyl-1-oxo-8-[(2,2,2-trifluoroethylamino)methyl]-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate.A mixture of tert-butyl10-methyl-8-(methylsulfonyloxymethyl)-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(300.00 mg, 700.12 μmol, 1.00 eq) and 2,2,2-trifluoroethanamine (1.39 g,14.00 mmol, 1.10 mL, 20.00 eq) in DMSO (8.00 mL) was heated to 116° C.in sealed tube for 16 h. LCMS showed starting material/desired product:˜1/2. another batch of 2,2,2-trifluoroethanamine (1.39 g, 14.00 mmol,1.10 mL, 20.00 eq) was added and the mixture was heated to 116° C. insealed tube for another 16 h. LCMS showed no starting material and majordesired product. The mixture was diluted with EtOAc (50 mL) and washedwith brine (50 mL, three times). The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo, which was purified byprep-TLC to afford the title compound (164.00 mg, 372.51 μmol, 53.21%yield, 98% purity) as white solid. LCMS: 454 [M+23].

Step 2.10-methyl-8-[(2,2,2-trifluoroethylamino)methyl]-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one.To a solution of tert-butyl10-methyl-11-oxo-8-[(2,2,2-trifluoroethylamino)methyl]-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxylate(174.00 mg, 403.29 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08g, 27.01 mmol, 2.00 mL, 66.98 eq), and the mixture was stirred at 30° C.for 1 h. The mixture was concentrated in vacuo to afford the titlecompound (228.00 mg, 407.59 μmol, 101.07% yield, 2TFA) as yellow oil,which was used directly for the next step.

Step 3.N-(3-cyano-4-fluorophenyl)-10-methyl-1-oxo-8-(((2,2,2-trifluoroethyl)amino)methyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. A mixture of10-methyl-8-[(2,2,2-trifluoroethylamino)methyl]-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one(114.00 mg, 203.80 μmol, 1.00 eq, 2TFA), Et₃N (123.74 mg, 1.22 mmol,169.51 μL, 6.00 eq) and phenyl N-(3-cyano-4-fluoro-phenyl)carbamate(44.39 mg, 173.23 mol, 0.85 eq) in DCM (4.00 mL) was stirred at 30° C.for 2 h. LCMS indicated the starting material was consumed completelyand major desired product. The mixture was concentrated in vacuo, whichwas purified by prep-HPLC (base) two times to afford the title compound(36.00 mg, 72.95 μmol, 35.80% yield) as yellow solid.

LCMS: 494 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (m, 1H), 7.60 (m, 1H),7.15 (t, J=8.8 Hz, 1H), 6.83 (s, 1H), 4.70 (s, 2H), 4.37-4.51 (m, 1H),4.10-4.25 (m, 1H), 3.82-3.97 (m, 2H), 3.31-3.54 (m, 2H), 3.16-3.30 (m,5H), 2.86 (m, 4H), 2.50-2.63 (m, 1H), 1.32-1.42 (m, 1H).

Compound 121:N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-1-oxo-8-(((2,2,2-trifluoroethyl)amino)methyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 120,using phenyl (4-fluoro-3-(trifluoromethyl)phenyl)carbamate in Step 3.LCMS: 537 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (m, 1H), 7.56-7.64 (m,1H), 7.14 (t, J=9.4 Hz, 1H), 6.78 (s, 1H), 4.70 (s, 2H), 4.43 (m, 1H),4.17 (m, 1H), 3.82-3.98 (m, 2H), 3.43-3.55 (m, 1H), 3.32-3.43 (m, 1H),3.19 (s, 5H), 2.71-2.93 (m, 4H), 2.48-2.64 (m, 1H), 1.28-1.45 (m, 1H).

Compound 122_D1:(3R,8S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R*)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer D1.

Step 1.tert-butyl(6R)-3-[[(2R,3S)-3-[tert-butyl(diphenyl)silyl]oxy-2-(hydroxymethyl)pent-4-enyl]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.To a mixture of(2S,3R)-3-[tert-butyl(diphenyl)silyl]oxy-2-(methylaminomethyl)pent-4-en-1-ol(Intermediate 21, 1.35 g, 2.71 mmol, 1.00 eq, TFA) and(6R)-5-tert-butoxycarbonyl-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylicacid (763.17 mg, 2.71 mmol, 1.00 eq) in DMF (8.00 mL) was added PYBOP(1.69 g, 3.26 mmol, 1.20 eq), HOBt (439.88 mg, 3.26 mmol, 1.20 eq) andDIPEA (1.40 g, 10.85 mmol, 1.90 mL, 4.00 eq), the reaction mixture wasstirred at 25° C. for 2 hours. Several new peaks were shown on LCMS andabout 30% of desired compound was detected. The reaction mixture wasdiluted with ethyl acetate (100 mL) and washed with water (80 mL*2), theorganic phase was dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by silica gel chromatography toafford the title compound (1.00 g, 3.09 mmol, 57.04% yield) as whitesolid.

Step 2. tert-butyl(R)-3-(((2S,3R)-3-((tert-butyldiphenylsilyl)oxy)-2-(((methylsulfonyl)oxy)methyl)pent-4-en-1-yl)(methyl)carbamoyl)-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate.To a mixture of tert-butyl(6R)-3-[[(2R,3S)-3-[tert-butyl(diphenyl)silyl]oxy-2-(hydroxymethyl)pent-4-enyl]-methylcarbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(350.00 mg, 541.05 μmol, 1.00 eq) and TEA (164.25 mg, 1.62 mmol, 225.00μL, 3.00 eq) in DCM (8.00 mL) was added MsCl (185.93 mg, 1.62 mmol,125.63 μL, 3.00 eq) at 0° C. under N₂, the reaction mixture was stirredat 25° C. for 30 minutes. TLC indicated starting material was consumedcompletely, and two major new spots with lower polarity was detected.The reaction was quenched with water (20 mL) and then extracted with DCM(50 mL*2), the combined organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuum to afford the title compound (700.00mg, crude) and as yellow oil, used in next step directly.

Step 3. tert-butyl(3R,8S)-8-((R)-1-((tert-butyldiphenylsilyl)oxy)allyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate. To a mixture oftert-butyl(6R)-3-[[(2R,3S)-3-[tert-butyl(diphenyl)silyl]oxy-2-(methylsulfonyloxymethyl)pent-4-enyl]-methylcarbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(700.00 mg, 965.54 μmol, 1.00 eq) and tert-butyl(6R)-3-[[(2R,3S)-3-[tert-butyl(diphenyl)silyl]oxy-2-(methylsulfonyloxymethyl)pent-4-enyl]-methyl-carbamoyl]-6-methyl-2-methylsulfonyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(965.54 μmol, 1.00 eq) in DMF (5.00 mL) was added Cs₂CO₃ (629.18 mg,1.93 mmol, 2.00 eq) and TBAI (35.66 mg, 96.55 μmol, 0.10 eq) under N₂,the reaction mixture was stirred at 25° C. for 16 hours. LCMS showed onemain peak with desired MS was detected. The reaction mixture was dilutedwith ethyl acetate (100 mL) and washed with water (50 mL*2), the organicphase was dried with anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by silica gel chromatography to affordthe title compound (350.00 mg, 556.55 μmol, 57.64% yield) as whitesolid.

Step 4. tert-butyl(3R,8S)-8-((R)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate. To a solution oftert-butyl(3R,8S)-8-((R)-1-((tert-butyldiphenylsilyl)oxy)allyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (700.00 mg, 1.11 mmol,1.00 eq) in THF (10.00 mL) was added TBAF (1 M, 2.22 mL, 2.00 eq), thereaction mixture was stirred at 25° C. for one hour. TLC indicatedstarting material was consumed completely and one major new spot withlarger polarity was detected. The reaction mixture was diluted withethyl acetate (100 mL) and washed with water (50 mL*2), the organicphase was dried with anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by silica gel chromatography to affordthe title compound (375.00 mg, 931.55 μmol, 83.92% yield, 97% purity) aswhite solid.

Step 5. tert-butyl(3R,8S)-8-((R)-1-((tert-butyldiphenylsilyl)oxy)allyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate D1 and D2. Compoundtert-butyl(3R,8S*)-8-((R*)-1-((tert-butyldiphenylsilyl)oxy)allyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (500.00 mg, 97% purity)was separated by SFC to get both diastereomers (D1: 190 mg and D2: 190mg)._SFC separation condition: Instrument: SFC 80; Column: AD-10 um;Mobile phase: A for CO₂ and B for MeOH (0.1% NH₃H₂O); Gradient: B 30%;Flow rate: 60 mL/min; Back pressure: 100 bar; Column temperature: 35°C.; Wavelength: 220 nm.

D1: ¹H NMR (400 MHz, CDCl₃) δ=5.85 (ddd, J=7.15, 10.16, 17.19 Hz, 1H),5.39 (d, J=17.19 Hz, 1H), 5.28-5.34 (m, 1H), 4.78-5.08 (m, 2H), 4.33(dd, J=7.47, 14.24 Hz, 1H), 4.09-4.22 (m, 2H), 4.02 (br dd, J=8.66,14.18 Hz, 1H), 3.56-3.64 (m, 1H), 3.46-3.55 (m, 1H), 3.19 (s, 3H), 2.91(br dd, J=5.77, 15.69 Hz, 1H), 2.56 (d, J=15.69 Hz, 1H), 2.42-2.52 (m,1H), 1.48 (s, 9H), 1.13 (d, J=7.03 Hz, 3H).

*Pure but unknown diastereomer D1.

D2: ¹H NMR (400 MHz, CDCl₃) δ=5.87 (ddd, J=7.09, 10.23, 17.19 Hz, 1H),5.41 (d, J=17.19 Hz, 1H), 5.32 (d, J=10.29 Hz, 1H), 4.79-5.08 (m, 2H),4.25-4.34 (m, 1H), 4.10-4.25 (m, 3H), 3.40-3.58 (m, 2H), 3.18 (s, 3H),2.93 (dd, J=5.83, 15.75 Hz, 1H), 2.47-2.59 (m, 2H), 1.48 (s, 9H), 1.12(d, J=6.90 Hz, 3H).

*Pure but unknown diastereomer D2.

Step 6.(3R,8S*)-8-((R*)-1-hydroxyallyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′: 3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_D1. To asolution of tert-butyl(3R,8S*)-8-((R*)-1-((tert-butyldiphenylsilyl)oxy)allyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1 (190.00 mg, 471.98μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (2.99 g, 26.20 mmol, 1.94mL, 55.52 eq), the reaction mixture was stirred at 25° C. for one hour.TLC indicated starting material was consumed completely. The reactionmixture was concentrated on a rotary evaporator to afford the titlecompound (190.00 mg, crude, TFA) as yellow oil, used in next stepdirectly.

*Pure but unknown diastereomer D1.

Step 7. D1:(3R,8S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R*)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide. To a mixture of(3R,8S*)-8-((R*)-1-hydroxyallyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_D1 (63.00 mg, 155.79 μmol, 1.00eq, TFA) in DCM (2.00 mL) was added TEA (63.06 mg, 623.16 μmol, 86.38μL, 4.00 eq), followed by phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (46.62 mg, 155.79 μmol, 1.00 eq), the reaction mixture wasstirred at 25° C. for 4 hours. LCMS showed one main peak with desired MSwas detected. Removed the solvent on a rotary evaporator. The residuewas purified by prep-HPLC(FA) to afford the title compound (56.00 mg,111.89 μmol, 71.82% yield, 99% purity) as white solid. LCMS (M+1): 496.¹H NMR (400 MHz, CDCl₃) δ=7.69 (dd, J=2.69, 6.11 Hz, 1H), 7.56-7.61 (m,1H), 7.13 (t, J=9.35 Hz, 1 H), 6.62 (s, 1H), 5.88 (ddd, J=7.15, 10.24,17.21 Hz, 1H), 5.42 (d, J=17.12 Hz, 1H), 5.34 (d, J=10.27 Hz, 1H), 5.15(t, J=6.42 Hz, 1H), 4.80 (d, J=15.16 Hz, 1H), 4.50 (d, J=15.28 Hz, 1H),4.36 (dd, J=7.46, 14.43 Hz, 1H), 4.10-4.18 (m, 2H), 3.49-3.65 (m, 2H),3.20 (s, 3H), 3.01 (dd, J=5.93, 15.71 Hz, 1H), 2.67 (d, J=16.14 Hz, 1H),2.49-2.57 (m, 1H), 1.79 (br s, 1H), 1.19 (d, J=6.85 Hz, 3H).

122˜124_D1 and D2 were prepared in a manner analogous to Compound 122.

Compound 122_D2:(3R,8S*)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((S*)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer D2.

LCMS (M+1): 496. ¹H NMR (400 MHz, CDCl₃) δ=7.70 (dd, J=2.69, 5.99 Hz,1H), 7.56-7.62 (m, 1H), 7.13 (t, J=9.41 Hz, 1H), 6.68 (br s, 1H), 5.88(ddd, J=7.09, 10.21, 17.18 Hz, 1H), 5.42 (d, J=17.12 Hz, 1H), 5.34 (d,J=10.27 Hz, 1H), 5.16 (quin, J=6.39 Hz, 1H), 4.84 (d, J=15.28 Hz, 1H),4.46 (d, J=15.16 Hz, 1H), 4.36 (dd, J=7.27, 14.37 Hz, 1H), 4.11-4.22 (m,2H), 3.47-3.63 (m, 2H), 3.20 (s, 3H), 3.03 (dd, J=6.05, 15.96 Hz, 1H),2.66 (d, J=15.77 Hz, 1H), 2.51-2.61 (m, 1H), 1.83 (br s, 1H), 1.18 (d,J=6.97 Hz, 3H).

Compound 123_D1:(3R,8S*)—N-(3-cyano-4-fluorophenyl)-8-((R*)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer D1.

LCMS (M+1): 453. ¹H NMR (400 MHz, CDCl₃) δ=7.80 (dd, J=2.75, 5.44 Hz,1H), 7.58 (ddd, J=2.87, 4.49, 9.02 Hz, 1H), 7.13 (t, J=8.68 Hz, 1H),6.71 (s, 1H), 5.88 (ddd, J=7.15, 10.15, 17.18 Hz, 1H), 5.42 (d, J=17.12Hz, 1H), 5.35 (d, J=10.27 Hz, 1H), 5.14 (quin, J=6.66 Hz, 1H), 4.80 (d,J=15.41 Hz, 1H), 4.49 (d, J=15.28 Hz, 1H), 4.36 (dd, J=7.40, 14.37 Hz,1H), 4.12-4.19 (m, 2H), 3.49-3.65 (m, 2H), 3.20 (s, 3H), 3.01 (dd,J=5.69, 15.96 Hz, 1H), 2.67 (d, J=15.77 Hz, 1H), 2.49-2.57 (m, 1H), 1.81(br s, 1H), 1.19 (d, J=6.97 Hz, 3H).

Compound 123_D2:(3R,8S*)—N-(3-cyano-4-fluorophenyl)-8-((S*)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer D2.

LCMS (M+1): 453. ¹H NMR (400 MHz, CDCl₃) δ=7.80 (dd, J=2.81, 5.50 Hz,1H), 7.58 (ddd, J=2.87, 4.55, 9.08 Hz, 1H), 7.13 (t, J=8.74 Hz, 1H),6.74 (s, 1H), 5.88 (ddd, J=7.03, 10.18, 17.15 Hz, 1H), 5.42 (d, J=17.12Hz, 1H), 5.34 (d, J=10.27 Hz, 1H), 5.14 (quin, J=6.30 Hz, 1H), 4.83 (d,J=15.28 Hz, 1H), 4.45 (d, J=15.28 Hz, 1H), 4.36 (dd, J=7.27, 14.37 Hz,1H), 4.12-4.22 (m, 2H), 3.48-3.63 (m, 2H), 3.20 (s, 3H), 3.02 (dd,J=5.81, 15.71 Hz, 1H), 2.66 (d, J=15.53 Hz, 1H), 2.52-2.60 (m, 1H), 1.82(br s, 1H), 1.18 (d, J=6.97 Hz, 3H).

Compound 124_D1:(3R,8S*)—N-(3-bromo-4-fluorophenvl)-8-((R*)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.

*Pure but unknown diastereomer D1.

LCMS (M+1): 506/508. ¹H NMR (400 MHz, CDCl₃) δ=7.74 (dd, J=2.63, 6.05Hz, 1H), 7.23-7.26 (m, 1H), 7.04 (t, J=8.56 Hz, 1H), 6.52 (s, 1H), 5.87(ddd, J=7.15, 10.24, 17.21 Hz, 1H), 5.42 (d, J=17.24 Hz, 1H), 5.34 (d,J=10.39 Hz, 1H), 5.10-5.17 (m, 1H), 4.78 (d, J=15.41 Hz, 1H), 4.48 (d,J=15.16 Hz, 1H), 4.36 (dd, J=7.46, 14.31 Hz, 1H), 4.09-4.18 (m, 2H),3.48-3.65 (m, 2H), 3.20 (s, 3H), 3.00 (dd, J=5.75, 15.53 Hz, 1H), 2.66(d, J=16.02 Hz, 1H), 2.48-2.57 (m, 1H), 1.79 (br s, 1H), 1.18 (d, J=6.97Hz, 3H).

Compound 124_D2:(3R,8S*)—N-(3-bromo-4-fluorophenvl)-8-((S*)-1-hydroxyallyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer D2.

LCMS (M+1): 506/508. ¹H NMR (400 MHz, CDCl₃) δ=7.75 (dd, J=2.69, 6.11Hz, 1H), 7.23-7.27 (m, 1H), 7.04 (t, J=8.50 Hz, 1H), 6.53 (s, 1H), 5.88(ddd, J=7.03, 10.15, 17.18 Hz, 1H), 5.42 (d, J=17.12 Hz, 1H), 5.34 (d,J=10.27 Hz, 1H), 5.11-5.18 (m, 1H), 4.81 (d, J=15.28 Hz, 1H), 4.45 (d,J=15.16 Hz, 1H), 4.32-4.39 (m, 1H), 4.12-4.23 (m, 2H), 3.48-3.62 (m,2H), 3.20 (s, 3H), 3.02 (dd, J=5.87, 15.89 Hz, 1H), 2.65 (d, J=15.53 Hz,1H), 2.51-2.60 (m, 1H), 1.81 (br s, 1H), 1.17 (d, J=6.97 Hz, 3H).

Compound 125_E1:(R*)—N-(5-bromo-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS: 547/549 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (t, J=7.95 Hz, 1H),6.93 (m, 1H), 6.58 (br d, J=2.81 Hz, 1H), 5.67-6.02 (m, 1H), 4.70 (s,2H), 4.12-4.45 (m, 2H), 3.74-3.94 (m, 2H), 3.28-3.50 (m, 2H), 3.18 (s,3H), 2.93-3.06 (m, 2H), 2.85 (t, J=5.75 Hz, 2H), 2.67-2.80 (m, 2H),2.49-2.61 (m, 1H).

Compound 125_E2:(S*)—N-(5-bromo-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8.9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS: 547/549 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (t, J=7.89 Hz, 1H),6.93 (dd, J=7.95, 10.64 Hz, 1H), 6.57 (br d, J=2.93 Hz, 1H), 5.67-6.02(m, 1H), 4.70 (s, 2H), 4.14-4.45 (m, 2H), 3.76-3.93 (m, 2H), 3.28-3.49(m, 2H), 3.18 (s, 3H), 2.93-3.08 (m, 1H), 2.91-3.00 (m, 1H), 2.85 (t,J=5.81 Hz, 2H), 2.75 (m, 2H), 2.46-2.60 (m, 1H).

Compound 126_E1:(R*)—N-(5-chloro-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3.4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS: 503/505 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (t, J=8.03 Hz, 1H),6.94 (m, 1H), 6.59 (br d, J=3.01 Hz, 1H), 5.65-6.02 (m, 1H), 4.70 (s,2H), 4.40 (m, 1H), 4.17 (m, 1H), 3.76-3.93 (m, 2H), 3.28-3.50 (m, 2H),3.18 (s, 3H), 2.93-3.08 (m, 2H), 2.85 (t, J=5.77 Hz, 2H), 2.75 (dq,J=7.47, 11.94 Hz, 2H), 2.48-2.62 (m, 1H).

Compound 126_E2:(S*)—N-(5-chloro-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8.9.10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS: 503/505 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (t, J=8.03 Hz, 1H),6.94 (dd, J=8.41, 10.54 Hz, 1H), 6.61 (br d, J=2.89 Hz, 1H), 5.67-6.02(m, 1H), 4.70 (s, 2H), 4.40 (m, 1H),4.17 ((m, 1H), 3.77-3.94 (m, 2H),3.28-3.50 (m, 2H), 3.17 (s, 3H), 2.92-3.06 (m, 2H), 2.85 (t, J=5.77 Hz,2H), 2.65-2.80 (m, 2H), 2.48-2.62 (m, 1H).

Compound 127_E1:(R*)—N-(3-cyano-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS: 494 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 8.27 (dt, J=5.77, 9.16 Hz,1H), 6.97-7.05 (m, 1H), 6.66 (br d, J=2.51 Hz, 1H), 5.67-6.02 (m, 1H),4.72 (s, 2H), 4.40 (m, 1H), 4.17 (m, 1H), 3.78-3.94 (m, 2H), 3.29-3.50(m, 2H), 3.18 (s, 3H), 2.92-3.07 (m, 2H), 2.86 (t, J=5.84 Hz, 2H),2.67-2.80 (m, 2H), 2.50-2.62 (m, 1H).

Compound 127_E2:(S*)—N-(3-cyano-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS: 494 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.76 (dt, J=5.99, 8.93Hz, 1H), 7.17-7.26 (m, 1H), 6.21-6.57 (m, 1H), 4.72 (s, 2H), 4.54 (m,1H), 4.36 (m, 1H), 3.76-3.97 (m, 2H), 3.54-3.74 (m, 3H), 3.08-3.27 (m,5H), 3.00 (br s, 1H), 2.86 (br t, =5.56 Hz, 2H).

Compound 128_E1:(R*)—N-(3-chloro-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS: 503/505 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.34 (dt, J=5.62,8.74 Hz, 1H), 7.08 (dt, J=1.90, 8.83 Hz, 1H), 6.21-6.54 (m, 1H),4.63-4.77 (m, 2H), 4.53 (m, 1H), 4.34 (m, 1H), 3.75-3.95 (m, 2H),3.53-3.72 (m, 3H), 3.08-3.27 (m, 5H), 2.98 (br s, 1H), 2.84 (t, J=5.75Hz, 2H).

Compound 128_E2:(S*)—N-(3-chloro-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS: 503/505 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (dt, J=5.50, 8.93Hz, 1H), 6.90-7.00 (m, 1H), 6.62 (br d, J=2.32 Hz, 1H), 5.66-6.01 (m,1H), 4.71 (s, 2H), 4.40 (dd, J=6.85, 14.31 Hz, 1H), 4.17 (m, 1H),3.74-3.94 (m, 2H), 3.26-3.49 (m, 2H), 3.06-3.22 (m, 3H), 2.91-3.05 (m,2H), 2.85 (t, J=5.75 Hz, 2H), 2.65-2.80 (m, 2H), 2.49-2.59 (m, 1H).

Compound 129_E1:(R*)—N-(3-bromo-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS: 547/549 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (dt, J=5.58, 8.94Hz, 1H), 6.94 (m, 1H), 6.59 (d, J=2.76 Hz, 1H), 5.66-6.03 (m, 1H), 4.71(s, 2H), 4.40 (m, 1H), 4.17 (m, 1H), 3.77-3.93 (m, 2H), 3.28-3.49 (m,2H), 3.18 (s, 3H), 2.91-3.08 (m, 2H), 2.85 (t, J=5.77 Hz, 2H), 2.75 (m,2H), 2.49-2.61 (m, 1H).

Compound 129_E2:(S*)—N-(3-bromo-2,4-difluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS: 547/549 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.93 (dt,J=5.75, 8.86 Hz, 1H), 6.89-7.00 (m, 1H), 6.58 (br s, 1H), 5.68-6.02 (m,1H), 4.71 (s, 2H), 4.12-4.44 (m, 2H), 3.77-3.93 (m, 2H), 3.28-3.50 (m,2H), 3.18 (s, 3H), 2.95-3.08 (m, 2H), 2.85 (t, J=5.81 Hz, 2H), 2.70-2.82(m, 2H), 2.51-2.63 (m, 1H).

Compound 130_E1:(R*)—N-(3-bromo-4-fluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS: 529/531 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.68-7.75 (m, 1H),7.33 (m, 1H), 7.11 (t, J=8.74 Hz, 1H), 6.19-6.52 (m, 1H), 4.67 (d,J=1.96 Hz, 2H), 4.51 (m, 1H), 4.33 (mz, 1H), 3.71-3.93 (m, 2H),3.51-3.70 (m, 3H), 3.07-3.26 (m, 5H), 2.90-3.03 (m, 1H), 2.82 (br t,J=5.62 Hz, 2H).

Compound 130_E2:(S*)—N-(3-bromo-4-fluorophenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS: 529/531 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.72 (dd,J=2.64, 6.02 Hz, 1H), 7.23-7.26 (m, 1H), 7.00-7.07 (m, 1H), 6.52-6.64(m, 1H), 6.58 (s, 1H), 5.66-6.05 (m, 1H), 4.67 (s, 2H), 4.41 (m, 1H),4.18 (dd, J=5.40, 14.56 Hz, 1H), 3.77-3.93 (m, 2H), 3.26-3.51 (m, 2H),3.18 (s, 3H), 2.94-3.09 (m, 2H), 2.84 (t, J=5.71 Hz, 2H), 2.65-2.80 (m,2H), 2.52-2.63 (m, 1H).

Compound 131_E1:(R*)—N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-1-oxo-1,3,47,89,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E1.

LCMS: 537 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.68 (dt, J=5.62, 8.68Hz, 1H), 7.14 (t, J=9.72 Hz, 1H), 6.19-6.52 (m, 1H), 4.70 (d, J=2.32 Hz,2H), 4.51 (m, 1H), 4.33 (m, 1H), 3.73-3.95 (m, 2H), 3.52-3.70 (m, 3H),3.09-3.27 (m, 5H), 2.98 (br s, 1H), 2.83 (br t, J=5.75 Hz, 2H).

Compound 131_E2:(S*)—N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8-(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

*Pure but unknown diastereomer E2.

LCMS: 537 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (dt, J=5.46, 8.94 Hz,1H), 6.98 (t, J=8.85 Hz, 1H), 6.65 (br d, J=3.01 Hz, 1H), 5.66-6.01 (m,1H), 4.72 (s, 2H), 4.40 (m, 1H), 4.17 (m, 1H), 3.77-3.95 (m, 2H),3.29-3.49 (m, 2H), 3.18 (s, 3H), 3.00 (m, 2H), 2.86 (t, J=5.71 Hz, 2H),2.67-2.80 (m, 2H), 2.50-2.60 (m, 1H).

Compound 132:N-(3-chloro-4-fluorophenyl)-3-hydroxy-10′-methyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide

To a solution of3′-hydroxy-10-methyl-spiro[1,2,3,4,7,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-8,1′-cyclobutane]-11-one(Intermediate 24, 30.00 mg, 76.85 μmol, 1.00 eq, TFA) in DCM (4.00 mL)was added TEA (38.88 mg, 384.25 μmol, 53.26 μL, 5.00 eq), followed byphenyl N-(3-chloro-4-fluoro-phenyl)carbamate (20.42 mg, 76.85 μmol, 1.00eq). The mixture was stirred at 20° C. for 1 hr. LCMS showed one mainpeak with desired Ms detected. The mixture was concentrated in vacuum.The residue was purified by prep-HPLC (FA) to afford the title compound(24.00 mg, 53.58 μmol, 69.73% yield) as white solid. LCMS: 448[M+1]. HNMR (400 MHz, METHANOL-d₄) 6=7.60 (dd, J=2.63, 6.66 Hz, 1H), 7.27-7.33(m, 1H), 7.09-7.18 (m, 1H), 4.68 (s, 2H), 4.34-4.42 (m, 1H), 4.32 (s,2H), 3.83 (t, J=5.81 Hz, 2H), 3.41 (s, 2H), 3.18 (s, 3H), 2.82 (t,J=5.81 Hz, 2H), 2.38-2.49 (m, 2H), 1.87-1.98 (m, 2H).

Compound 133_D1:(3R,8R*)-8-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide_D1

Step 1. 2-(tert-butyl) 8-ethyl(3R)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8.9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,8-dicarboxylate. To a solution of LDA (1M, 959.45 μL, 1.30 eq) in THF (2.00 mL) was added a solution of2-(tert-butyl) 8-ethyl(3R)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,8-dicarboxylate(300.00 mg, 738.04 μmol, 1.00 eq) in THF (2.00 mL) at −78° C. Themixture was stirred at −78° C. for 30 min. Then a solution of NFSI(279.28 mg, 885.65 μmol, 1.20 eq) in THF (2.00 mL) was added at −78° C.Then the mixture was stirred at −78° C. for 1 hr. The reaction mixturewas quenched with saturated NH₄Cl (10 mL) and extracted with EtOAc (80mL*2). The combined organic layers were dried over Na₂SO₄, filtrated andconcentrated in vacuum. The residue was purified column chromatography(PE:EA:30%50%) to afford the title compound (250.00 mg, 512.40 μmol,69.43% yield, 87% purity) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) 6=4.72 (dd, J=15.1, 17.8 Hz, 1H), 4.59-4.42 (m, 3H),4.33-4.21 (m, 2H), 3.86-3.73 (m, 1H), 3.70-3.49 (m, 3H), 3.11 (s, 3H),2.69 (br s, 2H), 1.41 (s, 9H), 1.29 (t, J=7.2 Hz, 3H).

Step 2. tert-Butyl(3R)-8-fluoro-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1 and tert-Butyl(3R)-8-fluoro-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D2.To a solution of 2-(tert-butyl) 8-ethyl(3R)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,8-dicarboxylate(230.00 mg, 541.85 μmol, 1.00 eq) in THF (6.00 mL) was added LiBH₄(35.40 mg, 1.63 mmol, 3.00 eq) with stirring at 0° C. for 1 h. Themixture was poured into the 20 mL of saturated NH₄Cl and extracted withEtOAc (20 mL*3), and then the combined organic phase was washed withbrine (20 mL*1), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was combined with a 30 mg (pilot reaction) andpurified by prep-TLC (PE: EtOAc=1:2) to obtain two diastereomers of thetitle compound: 45 mg tert-butyl(3R)-8-fluoro-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylateas colorless oil and 120 mg of and tert-Butyl(3R)-8-fluoro-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D2as a white solid.

Step 3.(3R)-8-fluoro-8-(hydroxymethyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_D1and(3R)-8-fluoro-8-(hydroxymethyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_D2To a solution of tert-butyl(3R)-8-fluoro-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(45.00 mg, 117.67 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (462.00mg, 4.05 mmol, 300.00 μL, 34.43 eq) at 15° C. with stirring for 1 h. Themixture was concentrated in vacuo. The residue was not purified. Thetitle compound (47.00 mg, crude, TFA) was obtained as yellow oil anddirectly used in the next step.

Step 4.(3R,8R*)-8-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide_D1.To a solution of(3R)-8-fluoro-8-(hydroxymethyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_D1(47.00 mg, 118.59 μmol, 1.00 eq, TFA) and phenylN-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (35.48 mg, 118.59 μmol,1.00 eq) in DCM (5.00 mL) was added TEA (72.00 mg, 711.54 μmol, 98.63μL, 6.00 eq) at 20° C. with stirring for 2 h. The mixture wasconcentrated in vacuo. The residue was purified by prep-HPLC(FA) toobtain the title compound (34.00 mg, 69.76 μmol, 58.82% yield) as whitesolid. LCMS: 488 [M+1]; ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (dd,J=2.76, 6.15 Hz, 1H), 7.54-7.62 (m, 1H), 7.13 (t, J=9.35 Hz, 1H), 6.55(s, 1H), 5.07-5.17 (m, 1H), 4.81 (d, J=15.56 Hz, 1H), 4.39-4.58 (m, 3H),3.75-3.97 (m, 2H), 3.63 (d, J=5.90 Hz, 1H), 3.59 (s, 1H), 3.23 (s, 3H),3.01 (dd, J=5.83, 16.12 Hz, 1H), 2.69 (d, J=16.06 Hz, 1H), 2.01-2.12 (m,1H), 1.20 (d, J=6.90 Hz, 3H).

Compound 133_D2:(3R,8S*)-8-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide_D2

The title compound was prepared in a manner analogous to Compound133_D1. LCMS: 488 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 6=7.70 (dd,J=2.70, 6.09 Hz, 1H), 7.56-7.64 (m, 1H), 7.27 (s, 3H), 7.13 (t, J=9.35Hz, 1H), 6.74 (br s, 1H), 5.10-5.20 (m, 1H), 4.89 (d, J=15.56 Hz, 1H),4.40-4.52 (m, 3H), 3.77-3.98 (m, 2H), 3.64 (d, J=2.89 Hz, 1H), 3.60 (s,1H), 3.22 (s, 3H), 3.03 (dd, J=6.02, 15.94 Hz, 1H), 2.67 (d, J=16.19 Hz,1H), 2.20 (br s, 1H), 1.18 (d, J=6.90 Hz, 3H).

Compound 134 D1:(3R,8R)—N-(3-Cyano-4-fluorophenvl)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,41]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-Butyl(3R,8R)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a mixture of tert-butyl(3R,8R)-8-(methoxy(methyl)carbamoyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(400.00 mg, 901.56 μmol, 1 eq) in THE (6 mL) and MeOH (6 mL) was addedNaBH₄ (68.21 mg, 1.80 mmol, 2 eq) in one portion at 0° C. under N₂. Themixture was stirred at 0° C. for 3 hours. The mixture was poured intowater (10 mL) and stirred for 1 min. The aqueous phase was extractedwith DCM (20 mL*2). The combined organic layers were washed with brine(15 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by silica gel chromatography (100-200mesh silica gel, Dichloromethane: Methanol=100/1, 20/1) to afford thetitle compound (328 mg, 900.01 μmol, 99.83% yield, 100% purity) asyellow solid. LCMS: 365 [M+1].

Step 2. tert-Butyl(3R,8R)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a mixture of tert-butyl(3R,8R)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(100.00 mg, 274.39 μmol, 1 eq) in THF (1 mL) was added NaH (21.95 mg,548.79 μmol, 60% purity, 2 eq) in one portion at −20° C. under N₂. Themixture was stirred at −20° C. for 30 min, then 2,2-difluoroethyltrifluoromethanesulfonate (176.25 mg, 823.18 μmol, 3 eq) was added tothe mixture. The mixture was stirred at −20° C. for 2 hours. The mixturewas poured into water (15 mL) and stirred for 1 min. The aqueous phasewas extracted with ethyl acetate (25 mL*2). The combined organic layerswere washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by prep-TLC (Ethylacetate: Petroleum ether=2/1) to afford the title compound (107 mg,249.72 μmol, 91.01% yield, 100% purity) as a yellow solid. LCMS: 429[M+1].

Step 3.(3R,8R)-8-((2,2-Difluoroethoxy)methyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one.To a solution of tert-butyl(3R,8R)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(160.00 mg, 373.42 μmol, 1.00 eq) in DCM (2 mL) was added TFA (4.39 g,38.48 mmol, 2.85 mL, 103.04 eq) under N₂. The mixture was stirred at 30°C. for 2 hours. The mixture was concentrated in vacuum to afford thetitle compound (166 mg, crude) as yellow oil.

Step 4.(3R,8R)—N-(3-Cyano-4-fluorophenvl)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a mixture of(3R,8R)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(61.61 mg, 187.62 μmol, 1 eq, TFA) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (53.42 mg, 187.62 μmol, 1 eq) inDCM (6.00 mL) was added TEA (189.85 mg, 1.88 mmol, 261.15 μL, 10.00 eq)under N₂. The mixture was stirred at 30° C. for 10 hours. The residuewas poured into water (10 mL) and stirred for 2 min. The aqueous phasewas extracted with ethyl acetate (10 mL*2). The combined organic layerswere washed with brine (5 mL*2), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by prep-HPLC(FA) toafford the title compound (76 mg, 152.63 μmol, 81.35% yield, 98.5%purity) as a white solid. LCMS: 491 [M+1]. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.79 (dd, J=2.81, 5.50 Hz, 1H), 7.51-7.60 (m, 1H), 7.14(t, J=8.74 Hz, 1H), 6.60 (s, 1H), 5.72-6.08 (m, 1H), 5.08-5.19 (m, 1H),4.80 (d, J=15.41 Hz, 1H), 4.38-4.53 (m, 2H), 4.13 (dd, J=6.97, 14.31 Hz,1H), 3.49-3.84 (m, 5H), 3.37 (d, J=6.24 Hz, 1H), 3.18 (s, 3H), 3.00 (d,J=5.99 Hz, 1H), 2.82 (br d, J=6.36 Hz, 1H), 2.68 (d, J=16.26 Hz, 1H),1.19 (d, J=6.97 Hz, 3H).

Compound 135_D1:(3R,8R)-8-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

To a mixture of(3R,8R)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(61.61 mg, 187.62 μmol, 1 eq, TFA) and phenylN-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (56.14 mg, 187.62 μmol,1 eq) in DCM (6.00 mL) was added TEA (189.85 mg, 1.88 mmol, 261.15 μL,10.00 eq) under N₂. The mixture was stirred at 30° C. for 10 hours. Theresidue was poured into water (10 mL) and stirred for 2 min. The aqueousphase was extracted with ethyl acetate (10 mL*2). The combined organiclayers were washed with brine (5 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to afford the title compound (71 mg, 133.09 μmol, 70.94%yield, 100% purity) as a white solid. LCMS: 534 [M+1] ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.68 (dd, J=2.75, 6.17 Hz, 1H), 7.55-7.62 (m, 1H), 7.13(t, J=9.41 Hz, 1H), 6.55 (s, 1H), 5.72-6.08 (m, 1H), 5.15 (t, J=6.30 Hz,1H), 4.81 (d, J=15.41 Hz, 1H), 4.40-4.53 (m, 2H), 4.12 (dd, J=7.15,14.24 Hz, 1H), 3.49-3.82 (m, 5H), 3.35 (dd, J=5.93, 14.98 Hz, 1H), 3.02(dd, J=5.87, 15.65 Hz, 1H), 2.75-2.87 (m, 1H), 2.67 (d, J=15.89 Hz, 1H),1.19 (d, J=6.85 Hz, 3H).

Compound 134_D2:(3R,8S)—N-(3-cyano-4-fluorophenvl)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-Butyl(3R,8S)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate. To a solution of tert-butyl(3R,8S)-8-(methoxy(methyl)carbamoyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(300 mg, 711.76 μmol, 1 eq) in THF (6 mL) and MeOH (6 mL) was addedNaBH₄ (53.85 mg, 1.42 mmol, 2 eq) at 0° C. The solution was stirred at25° C. for 16 hr. The solution was poured into water (30 mL). Themixture extracted with ethyl acetate (20 mL*2). The combined organiclayers were washed with brine (20 mL), dried with anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography. The title compound (230 mg, 602.71 μmol, 84.68% yield,95.5% purity) was obtained as yellow oil. LCMS: 365 [M+1].

Step 2. tert-Butyl(3R,8S)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate. To a solution of tert-butyl(3R,8S)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(230 mg, 631.11 μmol, 1 eq) in THF (10 mL) was added NaH (50.49 mg, 1.26mmol, 60% purity, 2 eq) at −20° C. The solution was stirred at −20° C.for 30 min. Then 2,2,2-difluoroethyl trifluoromethanesulfonate (405.38mg, 1.89 mmol, 3 eq) was added, the solution was stirred at −15° C. for2 hr. The solution was poured into water (30 mL). The mixture extractedwith ethyl acetate (20 mL*2). The combined organic layers were washedwith brine (20 mL*3), dried with anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC. The title compound(190 mg, 443.44 μmol, 70.26% yield) was obtained as yellow oil.

Step 3.(3R,8S)-8-((2,2-Difluoroethoxy)methyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one.To a solution of tert-butyl(3R,8S)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(190 mg, 443.44 μmol, 1 eq) in DCM (5 mL) was added TFA (7.70 g, 67.53mmol, 5.00 mL, 152.29 eq). The solution was stirred at 25° C. for 30min. The solution was concentrated. The title compound (196 mg, crude,TFA) was obtained as yellow oil.

Step 4.(3R,8S)—N-(3-Cyano-4-fluorophenyl)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(3R,8S)-8-((2,2-difluoroethoxy)methyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(98 mg, 221.53 μmol, 1 eq, TFA) in DCM (2 mL) was added TEA (67.25 mg,664.59 μmol, 92.50 μL, 3 eq) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (56.76 mg, 221.53 μmol, 1 eq). Thesolution was stirred at 25° C. for 16 hr. TEA (67.25 mg, 664.59 μmol,92.50 μL, 3 eq) was added. The solution was stirred at 25° C. for 16 hr.The solution was concentrated. The residue was purified by prep-HPLC(FA). The title compound (47.37 mg, 94.32 μmol, 42.58% yield, 97.66%purity) was obtained as white solid. LCMS: 491 [M+1]; ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.79 (dd, J=2.81, 5.38 Hz, 1H), 7.60 (ddd, J=2.87, 4.55,9.08 Hz, 1H), 7.13 (t, J=8.68 Hz, 1H), 6.86 (s, 1H), 5.68-6.07 (m, 1H),5.13 (quin, J=6.57 Hz, 1H), 4.84 (d, J=15.41 Hz, 1H), 4.36-4.52 (m, 2H),4.15 (dd, J=5.93, 14.37 Hz, 1H), 3.48-3.83 (m, 5H), 3.33 (dd, J=7.09,15.04 Hz, 1H), 3.18 (s, 3H), 3.01 (dd, J=5.75, 16.02 Hz, 1H), 2.82 (td,J=6.40, 12.75 Hz, 1H), 2.66 (d, J=15.89 Hz, 1H), 1.18 (d, J=6.85 Hz,3H).

Compound 135_D2:(3R,8S)-8-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

To a solution of(3R,8S)-8-((,2-difluoroethoxy)methyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(98 mg, 221.53 μmol, 1 eq, TFA) in DCM (2 mL) was added TEA (67.25 mg,664.59 μmol, 92.50 μL, 3 eq) and phenylN-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (66.29 mg, 221.53 μmol,1 eq). The solution was stirred at 25° C. for 16 hr. TEA (67.25 mg,664.59 μmol, 92.50 μL, 3 eq) was added. The solution was stirred at 25°C. for 16 hr. The solution was concentrated. The residue was purified byprep-HPLC (FA). The title compound (68.35 mg, 122.53 μmol, 55.31% yield,95.63% purity) was obtained as a white solid. LCMS: 534 [M+1]; ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.69 (dd, J=2.63, 6.05 Hz, 1H), 7.54-7.64 (m,1H), 7.12 (t, J=9.41 Hz, 1H), 6.81 (s, 1H), 5.70-6.08 (m, 1H), 5.14(quin, J=6.42 Hz, 1H), 4.84 (d, J=15.41 Hz, 1H), 4.33-4.53 (m, 2H), 4.16(dd, J=5.75, 14.31 Hz, 1H), 3.43-3.88 (m, 5H), 3.32 (dd, J=7.27, 14.98Hz, 1H), 3.17 (s, 3H), 3.02 (dd, J=5.81, 15.83 Hz, 1H), 2.74-2.89 (m,1H), 2.66 (d, J=15.77 Hz, 1H), 1.17 (d, J=6.97 Hz, 3H).

Compound 136:(R)—N-(3-cyano-4-fluorophenyl)-8,8-difluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-Butyl(R)-3,10-dimethyl-8,11-dioxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a solution of tert-butyl(R)-3,10-dimethyl-8-methylene-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(370.00 mg, 1.07 mmol, 1.00 eq) in THF (10.00 mL) and H₂O (5.00 mL) wasadded OsO4 (27.20 mg, 107.00 μmol, 5.55 μL, 0.10 eq) and NaIO4 (686.59mg, 3.21 mmol, 177.87 μL, 3.00 eq) at 0° C. The mixture was stirred at15° C. for 16 hr. The mixture was diluted with EtOAc (60 mL) and washedwith saturated Na₂SO₃ (60 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to give brown oil. The resulting oilwas purified via silica gel column (EA/PE=5/1) to afford the titlecompound (200.00 mg, 539.61 μmol, 50.43% yield, 94% purity).

Step 2. tert-Butyl(R)-8,8-difluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a solution of tert-butyl(R)-3,10-dimethyl-8,11-dioxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(80.00 mg, 229.62 μmol, 1.00 eq) in DCM (3.00 mL) was added DAST (222.08mg, 1.38 mmol, 182.03 μL, 6.00 eq) slowly with stirring at −30° C. underN₂. The mixture was warmed to 15° C. with stirring for 16 h. The mixturewas quenched with 10 mL of water and extracted with DCM (15 mL*3). Thecombined organic layers were washed with brine (15 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by prep-TLC (DCM:MeOH=10:1) to afford the title compound (40.00mg, 97.19 μmol, 42.33% yield, 90% purity) as colorless oil.

Step 3.(R)-8,8-Difluoro-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one.To a solution of tert-butyl(R)-8,8-difluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(40.00 mg, 97.19 mol, 1.00 eq) in DCM (3.00 mL) was added TFA (462.00mg, 4.05 mmol, 300.00 μL, 41.69 eq) at 15° C., and the mixture wasstirring for 2 h. The mixture was concentrated in vacuum to afford thetitle compound (40.00 mg, crude, TFA) was obtained as yellow oil, whichwas not purified and directly used in the next step.

Step 4.(R)—N-(3-Cyano-4-fluorophenvl)-8,8-difluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(R)-8,8-difluoro-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(40.00 mg, 104.09 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA(63.20 mg, 624.54 μmol, 86.58 μL, 6.00 eq) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (32.00 mg, 124.91 μmol, 1.20 eq) at15° C., and then the mixture was stirring for 16 h. The mixture wasconcentrated in vacuum and purified by prep-HPLC (TFA) twice to give thetitle compound (18 mg, 39.96 μmol, 38.39% yield, 96% purity) as a whitesolid. LCMS: 433 [M+1]; ¹H NMR (400 MHz, CHLOROFORM-d) 6=7.76 (dd,J=2.82, 5.33 Hz, 1H), 7.60 (m, 1H), 7.15 (t, J=8.72 Hz, 1H), 6.67 (s,1H), 5.07-5.16 (m, 1H), 4.87 (d, J=15.69 Hz, 1H), 4.72 (t, J=12.42 Hz,2H), 4.47 (d, J=15.69 Hz, 1H), 3.68-3.79 (m, 2H), 3.25 (s, 3H), 3.04(dd, J=5.58, 16.12 Hz, 1H), 2.72 (d, J=15.56 Hz, 1H), 1.20 (d, J=6.90Hz, 3H).

Compound 137_D1:(3R,8R*)—N-(3-cyano-4-fluorophenyl)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide_D1

Step 1. tert-Butyl(3R)-8-hydroxy-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a solution of tert-butyl(R)-3,10-dimethyl-8,11-dioxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(120.00 mg, 344.43 μmol, 1.00 eq) in MeOH (5.00 mL) was added NaBH₄(39.09 mg, 1.03 mmol, 3.00 eq) at 0° C., and then the mixture was warmedto 15° C. with stirring for 1 h under N2 atmosphere. The mixture waspoured into ice-water (20 mL) and stirred at 5 min. The aqueous phasewas extracted with ethyl acetate (10 mL*3). The combined organic layerswere washed with brine (20 mL), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by prep-TLC(DCM:MeOH=10:1) to give the title compound (78.00 mg, 222.60 μmol,64.63% yield) as colorless oil.

Step 2. tert-Butyl(3R)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1and tert-butyl(3R)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,41]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D2.To a solution of tert-butyl(3R)-8-hydroxy-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(60.00 mg, 171.23 μmol, 1.00 eq) in DCM (1.00 mL) was added DAST (82.80mg, 513.68 μmol, 67.87 μL, 3.00 eq) drop wise at −30° C., and then themixture was warmed to 15° C. with stirring for 1 h. The mixture wascontinued to stir at 15° C. for another 1 h. The mixture was quenchedwith 10 mL of water and extracted with DCM (15 mL*3). The combinedorganic layers were washed with brine (15 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue with waspurified by prep-TLC (DCM:MeOH=10:1), following by SFC (SFC separationcondition: column: IC (250 mm*30 mm, 10 um); mobile phase: [0.1% NH₃H₂OMEOH]; B %: 25%-25%, 4.35 min; 90 min) separation to give twodiastereomers: 20 mg of tert-butyl(3R)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1and 18 mg of tert-butyl(3R)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D2as colorless oil.

Step 3.(3R)-8-Fluoro-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_D1.To a solution of tert-butyl(3R)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1(20 mg, 56.75 μmol, 1 eq) in DCM (1 mL) was added TFA (307.99 mg, 2.70mmol, 199.99 μL, 47.60 eq) dropwise at 15° C., and the mixture wasstirred for 1 h. The mixture was concentrated in vacuum to give thetitle compound (20.79 mg, crude, TFA) as yellow oil, which was notfurther purified and directly used in the next step.

Step 4.(3R,8R*)—N-(3-cyano-4-fluorophenvl)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide_D1.To a solution of(3R)-8-fluoro-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_D1(20.79 mg, 56.75 μmol, 1 eq, TFA) and TEA (34.46 mg, 340.52 μmol, 47.40μL, 6 eq) in DCM (1 mL) was added phenylN-(3-cyano-4-fluoro-phenyl)carbamate (18.91 mg, 73.78 μmol, 1.3 eq), andstirred at 15° C. for 16 h. The mixture was concentrated in vacuum, andwas purified by prep-HPLC(FA) to give the title compound (7.5 mg, 18.03μmol, 31.76% yield, 99.6% purity) as a white solid. LCMS: 415 [M+1]. ¹HNMR (400 MHz, CHLOROFORM-d) 6=7.80 (dd, J=2.82, 5.46 Hz, 1H), 7.56 (m,1H), 7.15 (t, J=8.66 Hz, 1H), 6.58 (s, 1H), 5.11-5.19 (m, 1H), 4.83 (d,J=15.69 Hz, 1H), 4.36-4.59 (m, 5H), 3.97-4.07 (m, 1H), 3.23 (s, 3H),3.04 (dd, J=6.21, 16.00 Hz, 1H), 2.72 (d, J=16.19 Hz, 1H), 1.19 (d,J=6.90 Hz, 3H).

Compound 137_D2:(3R,8S*)—N-(3-Cyano-4-fluorophenvl)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide_D2

The title compound was prepared in a manner analogous to Compound 246tert-butyl(3R)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D2.LCMS: 415 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 6=7.81 (dd, J=2.76, 5.40Hz, 1H), 7.59 (m, 1H), 7.27 (s, 2H), 7.15 (t, J=8.72 Hz, 1H), 6.67 (s,1H), 5.11-5.21 (m, 1H), 4.93 (d, J=15.56 Hz, 1H), 4.36-4.64 (m, 5H),3.95-4.09 (m, 1H), 3.23 (s, 3H), 3.06 (dd, J=5.58, 15.87 Hz, 1H), 2.70(d, J=15.81 Hz, 1H), 1.16 (d, J=6.90 Hz, 3H).

Compound 138:(3R,8R*)-8-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-Butyl(3R,8R)-8-hydroxy-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.Tert-butyl(5R)-11-hydroxy-5,13-dimethyl-14-oxo-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-diene-4-carboxylate (674 mg, 1.92 mmol, 1 eq) wasseparated via SFC to give both diastereomers: tert-butyl(3R,8R)-8-hydroxy-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1and (345 mg, 936.31 mol, 95.1% purity, t=1.66 min) and tert-butyl(3R,8R)-8-hydroxy-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D2(310 mg, 874.94 μmol, 45.49% yield, 98.9% purity, t=1.89 min) as whitesolid. SFC analysis condition: AD-3S_4_5_40_3 ML. Column: Chiralpak AD-3100×4.6 mm I.D., 3 um; Mobile phase: iso-propanol (0.05% DEA) in CO2from 5% to 40%; Flow rate: 3 mL/min Wavelength: 220 nm. SFC separationcondition: Column: AD (250 mm*30 mm, 10 um); Mobile phase: [0.1% NH₃H₂OIPA]; B %: 20%-20%,2.3 min; 150 min.

Step 2. tert-Butyl(3R,8S)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1.To a solution of resulting tert-butyl(3R,8R)-8-hydroxy-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1(150.00 mg, 428.07 μmol, 1 eq) in DCM (2 mL) was added DAST (207.00 mg,1.28 mmol, 169.67 μL, 3 eq) at −30° C. The mixture was stirred at −30°C. for 2 hr. The mixture was diluted with H₂O (20 mL) and extracted withDCM (20 mL*3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, EA: MeOH=10:1) to afford the title compound(89 mg, 250.78 μmol, 58.58% yield, 99.3% purity) as yellow oil andchecked by HPLC. SFC (IC-3S_3_5_40_3 ML Column: Chiralpak IC-3 100×4.6mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%Flow rate: 3 mL/min Wavelength: 220 nm) indicated that the resultingproduct was corresponding to first diastereomer D1.

Step 3.(3R,8S)-8-Fluoro-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_D1.To a solution of tert-butyl(3R,8S)-8-fluoro-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_D1(85.00 mg, 241.20 μmol, 1 eq) in DCM (5 mL) was added TFA (770.00 mg,6.75 mmol, 500.00 μL, 28.00 eq). The mixture was stirred at 16° C. for 2hr. The mixture was concentrated under reduced pressure to give thetitle compound (89 mg, crude, TFA) as yellow oil, which without furtherpurified and directly used in the next step.

Step 4.(3R,8R*)-8-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(3R,8S)-8-fluoro-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_D1(70 mg, 277.46 μmol, 1 eq, TFA) in DCM (5 mL) were added TEA (140.38 mg,1.39 mmol, 193.10 μL, 5 eq) and phenylN-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (83.02 mg, 277.46 μmol,1 eq). The mixture was stirred at 16° C. for 10 hr. The mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (FA) to give the title compound (54 mg, 118.06 μmol, 42.55%yield, 100% purity) as white solid. LCMS: 458 [M+1]. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.70 (dd, J=2.64, 6.15 Hz, 1H), 7.55-7.62 (m, 1H), 7.14(t, J=9.35 Hz, 1H), 6.62 (s, 1H), 5.17 (quin, J=6.84 Hz, 1H), 4.85 (d,J=15.69 Hz, 1H), 4.31-4.63 (m, 5H), 3.93-4.10 (m, 1H), 3.23 (s, 3H),3.05 (dd, J=6.02, 15.69 Hz, 1H), 2.71 (d, J=16.19 Hz, 1H), 1.19 (d,J=6.90 Hz, 3H).

Compound 139:(R)—N-(3-cyano-4-fluorophenvl)-3,8,8,10-tetramethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. N-(3-Hydroxy-2,2-dimethylpropyl)formamide. To a solution of3-amino-2,2-dimethyl-propan-1-ol (3.3 g, 31.99 mmol, 1 eq) in EtOH (60mL) was added HCOOEt (4.73 g, 63.98 mmol, 2 eq). The mixture was stirredat 80° C. for 6 hr. The mixture was concentrated in vacuum to afford thetitle compound (4.1 g, crude) as colorless oil, used in the next stepdirectly.

Step 2. 2,2-Dimethyl-3-(methylamino)propan-1-ol. To a solution ofN-(3-hydroxy-2,2-dimethyl-propyl)formamide (4 g, 30.49 mmol, 1 eq) inTHF (50 mL) at −40° C. was added LAH (1.50 g, 39.64 mmol, 1.3 eq)portionwise. Then the mixture was heated to 20° C. for 16 hr. Themixture was quenched by H₂O (1.5 mL), 15% NaOH (1.5 mL) and H₂O (3 mL).The mixture was filtered and concentrated in vacuum to afford the titlecompound (3.5 g, crude) as a white solid, used in the next stepdirectly.

Step 3. tert-Butyl(R)-3-((3-hydroxy-2,2-dimethylpropyl)(methyl)carbamoyl)-6-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of(R)-5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (1.5 g, 5.33 mmol, 1 eq) and2,2-dimethyl-3-(methylamino)propan-1-ol (812.34 mg, 6.93 mmol, 1.3 eq)in pyridine (15 mL) was added EDCI (1.23 g, 6.40 mmol, 1.2 eq). Themixture was heated to 40° C. for 16 hr. The mixture was extracted withEA (100 mL*3) and H₂O (100 mL). The combined organic layers were washedwith TN HCl (60 mL*3), filtered, dried over Na₂SO₄, concentrated invacuum. The residue was purified by flash silica chromatography(PE:EA:50%-100%) to afford the title compound (1.0 g, 2.63 mmol, 49.29%yield) as a white solid.

Step 4. tert-Butyl(R)-3-((2,2-dimethyl-3-((methylsulfonyl)oxy)propyl)(methyl)carbamoyl)-6-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of tert-butyl(R)-3-((3-hydroxy-2,2-dimethylpropyl)(methyl)carbamoyl)-6-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(800 mg, 2.10 mmol, 1 eq) in DCM (8 mL) was added DIEA (815.24 mg, 6.31mmol, 1.10 mL, 3 eq), followed by MsCl (289.03 mg, 2.52 mmol, 195.29 μL,1.2 eq) slowly at −10° C. The mixture was stirred at 10° C. for 10 min.Additional MsCl (240.85 mg, 2.10 mmol, 162.74 μL, 1 eq) was added andthe mixture was stirred at 10° C. for 10 min. The mixture was dilutedwith H₂O (20 mL) and extracted with DCM (20 mL). The organic layer waswashed with 0.5N HCl (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum to give the title compound (1.0 g, crude) as awhite solid used in the next step directly.

Step 5. tert-Butyl(R)-3,8,8,10-tetramethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a solution of tert-butyl(R)-3-((2,2-dimethyl-3-((methylsulfonyl)oxy)propyl)(methyl)carbamoyl)-6-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(1.0 g, 1.86 mmol, 1 eq) in THF (10 mL) was added NaH (149.07 mg, 3.73mmol, 60% purity, 2 eq) at 0° C. The mixture was stirred at 40° C. for16 hr. The mixture was heated to 40° C. for an additional 32 hr.Additional NaH (111.79 mg, 2.80 mmol, 60% purity, 1.5 eq) was added andthe mixture was heated to 40° C. for 48 hr. The mixture was poured intowater (10 mL) and extracted with EA (30 mL*3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel column chromatography (PE:EA:30%50%)to afford the title compound (670 mg, 1.85 mmol, 99.20% yield) as awhite solid.

Step 6.(R)-3.8,8,10-Tetramethyl-1.2.3.4.7.8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one.To a solution of tert-butyl(R)-3,8,8,10-tetramethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(160 mg, 441.42 μmol, 1 eq) in DCM (2 mL) was added TFA (3.08 g, 27.01mmol, 2 mL, 61.19 eq). The mixture was stirred at 15° C. for 1 hr. Themixture was concentrated in vacuum to afford the title compound (172 mg,crude, TFA) as brown oil, used in the next step directly.

Step 7.(R)—N-(3-Cyano-4-fluorophenvl)-3,8,8,10-tetramethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(R)-3,8,8,10-tetramethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(85 mg, 225.84 μmol, 1 eq, TFA) in DCM (2 mL) was added TEA (114.26 mg,1.13 mmol, 157.17 μL, 5 eq) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (57.87 mg, 225.84 μmol, 1 eq). Themixture was stirred at 15° C. for 16 hr. The mixture was concentrated invacuum. The residue was purified by prep-HPLC (FA) to afford the titlecompound (51.44 mg, 118.04 μmol, 52.27% yield, 97.4% purity) as a whitesolid.

LCMS: 425 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.81 (dd, J=2.76, 5.52Hz, 1H), 7.53-7.61 (m, 1H), 7.15 (t, J=8.72 Hz, 1H), 6.57 (s, 1H), 5.14(br t, J=6.90 Hz, 1H), 4.81 (d, J=15.43 Hz, 1H), 4.51 (d, J=15.31 Hz,1H), 4.04 (s, 2H), 3.22 (s, 3H), 3.00-3.17 (m, 3H), 2.70 (d, J=15.94 Hz,1H), 1.11-1.24 (m, 9H).

Compound 140:(R)—N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3,8,8,10-tetramethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 139,substituting phenyl (4-fluoro-3-(trifluoromethyl)phenyl)carbamate forphenyl N-(3-cyano-4-fluoro-phenyl)carbamate in Step 7. LCMS: 468 [M+1].¹H NMR (400 MHz, CHLOROFORM-d) δ=7.70 (dd, J=2.57, 6.21 Hz, 1H),7.56-7.63 (m, 1H), 7.15 (t, J=9.35 Hz, 1H), 6.54 (s, 1H), 5.08-5.21 (m,1H), 4.81 (d, J=15.31 Hz, 1H), 4.52 (d, J=15.18 Hz, 1H), 4.04 (s, 2H),3.22 (s, 3H), 3.11-3.18 (m, 1H), 2.99-3.09 (m, 2H), 2.70 (d, J=16.19 Hz,1H), 1.11-1.23 (m, 9H).

Compound 141:(R)—N-(3-Cyano-4-fluorophenvl)-3-hydroxy-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide

Step 1. tert-Butyl(R)-3-(((3-(benzyloxy)-1-(hydroxymethyl)cyclobutyl)methyl)(methyl)carbamoyl)-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate.To a mixture of [3-benzyloxy-1-(methylaminomethyl)cyclobutyl]methanol(1.6 g, 4.58 mmol, 1 eq, TFA) and(R)-5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (1.03 g, 3.66 mmol, 0.8 eq) in pyridine (10 mL) was added EDCI(1.05 g, 5.50 mmol, 1.2 eq), the reaction mixture was stirred at 40° C.for 16 hours. The reaction mixture was diluted with ethyl acetate (100mL) and washed with diluted HCl (1N, 80 mL*3), the organic phase wasdried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography. The title compound(835 mg, 98% purity) was obtained as yellow solid.

Step 2. tert-Butyl(R)-3-(((3-(benzyloxy)-1-(((methylsulfonyl)oxy)methyl)cyclobutyl)methyl)(methyl)carbamoyl)-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylateand tert-butyl(R)-3-(((3-(benzyloxy)-1-(((methylsulfonyl)oxy)methyl)cvclobutvl)methyl)(methyl)carbamovl)-6-methyl-2-(methylsulfonyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of tert-butyl(R)-3-(((3-(benzyloxy)-1-(hydroxymethyl)cyclobutyl)methyl)(methyl)carbamoyl)-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(612.24 mg, 1.20 mmol, 1.00 eq) in DCM (6 mL) were added DIEA (466.56mg, 3.61 mmol, 628.78 μL, 3 eq) and MsCl (206.76 mg, 1.81 mmol, 139.71μL, 1.5 eq). The mixture was stirred at 20° C. for 2 hr. Additional MsCl(206.76 mg, 1.81 mmol, 139.71 μL, 1.5 eq) was added and the mixture wasstirred at 20° C. for 1 hr. The mixture was extracted with DCM (30 mL*2)and H₂O (20 mL). The combined organic layers were washed 0.5 N HCl (10mL), dried over Na₂SO₄, filtered and concentrated in vacuum. To afford amixture of the title compounds as brown oil, used in the next stepdirectly.

Step 3. tert-Butyl(R)-3-(benzyloxy)-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate.To a solution of tert-butyl(R)-3-(((3-(benzyloxy)-1-(((methylsulfonyl)oxy)methyl)cyclobutyl)methyl)(methyl)carbamoyl)-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylateand tert-butyl(R)-3-(((3-(benzyloxy)-1-(((methylsulfonyl)oxy)methyl)cyclobutyl)methyl)(methyl)carbamoyl)-6-methyl-2-(methylsulfonyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(900 mg, 1.46 mmol, 1 eq) in THF (10 mL) was added NaH (234.15 mg, 5.85mmol, 60% purity, 4 eq) and NaI (43.87 mg, 292.68 μmol, 0.2 eq) at 0° C.The mixture was stirred at 40° C. for 16 hr. Additional NaH (234.12 mg,5.85 mmol, 60% purity, 4 eq) was added and the mixture was stirred at40° C. for 48 hr. The mixture was stirred at 40° C. for 16 hr. Themixture was combined with another batch and was quenched with H₂O (40mL) and extracted with EA (80 mL*3). The combined organic layer wasdried over Na₂SO₄, filtrated and concentrated in vacuum. The resultingresidue s combined with another batch of crude product and purified bycolumn chromatography (SiO₂, PE:EA=30%-60%) to give 350 mg desiredproduct totally as colorless oil.

Step 4. tert-Butyl(R)-3-hydroxy-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate.To a solution of tert-butyl(R)-3-(benzyloxy)-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate(350 mg, 728.26 μmol, 1.00 eq) in MeOH (10.00 mL) was added Pd/C (50 mg,728.26 μmol, 10% purity, 1.00 eq) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (20 psi) at 40° C. for 3 hours. The mixture was stirred underH₂ (20 psi) at 40° C. for 16 hours. The mixture was stirred under H₂ (50psi) at 25° C. for 16 hours. The mixture was diluted with MeOH (80 mL),filtrated and concentrated in vacuum to give the title compound (290 mg,crude) as white solid, which was used in the next step directly.

Step 5.(R)-3-Hydroxy-3′,10′-dimethyl-1′,2′,3′,4′,9′,10′-hexahydro-7′H,11′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin]-11′-one.To a solution of tert-butyl(R)-3-hydroxy-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate(55 mg, 140.85 μmol, 1 eq) in DCM (2 mL) was added TFA (2.82 g, 24.76mmol, 1.83 mL, 175.79 eq). The mixture was stirred at 15° C. for 0.5 hr.The mixture was concentrated in vacuo. The title compound (60 mg, crude,TFA) was obtained as brown oil, which was used in the next stepdirectly.

Step 6.(R)—N-(3-Cyano-4-fluorophenyl)-3-hydroxy-3′,10′-dimethyl-11′-oxo-1′,3′4′,9′10′11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide.To a solution of(R)-3-hydroxy-3′,10′-dimethyl-1′,2′,3′,4′,9′,10′-hexahydro-7′H,11′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin]-11′-one(58 mg, 143.43 μmol, 1 eq, TFA) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (36.75 mg, 143.43 μmol, 1 eq) inDCM (2 mL) was added TEA (72.57 mg, 717.14 μmol, 99.82 μL, 5 eq). Themixture was stirred at 15° C. for 30 min. The mixture was concentratedin vacuo. The residue was purified by prep-HPLC (FA). The title compound(25.02 mg, 54.65 μmol, 38.11% yield, 98.84% purity) was obtained aswhite solid. LCMS: 453 [M+1]. ¹H NMR (400 MHz, METHANOL-d4) δ=7.82 (dd,J 2.76, 5.65 Hz, 1H), 7.70 (ddd, J 2.76, 4.74, 9.19 Hz, 1H), 7.28 (t, J8.97 Hz, 1H), 4.94-5.04 (m, 2H), 4.31-4.41 (m, 4H), 3.43 (s, 2H), 3.19(s, 3H), 3.01 (dd, J 5.90, 15.81 Hz, 1H), 2.67 (d, J 15.94 Hz, 1H),2.40-2.50 (m, 2H), 1.98 (dd, J=7.84, 12.11 Hz, 1H), 1.89 (dd, J 7.15,12.67 Hz, 1H), 1.22 (d, J 6.90 Hz, 3H).

Compound 142:(R)—N-(3-Cyano-4-fluorophenyl)-3-fluoro-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide

Step 1. tert-Butyl (R)-3-fluoro-3′,10′-dimethyl-11′-oxo-1′3′,4′,9′10′11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate.To a solution of tert-butyl(R)-3-hydroxy-3′,10′-dimethyl-11‘-oxo-1’,3′,4′, 9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate(70 mg, 179.27 μmol, 1 eq) in DCM (1.5 mL) was added DAST (86.69 mg,537.81 μmol, 71.06 μL, 3 eq) at −40° C. The mixture was stirred at 0° C.for 1 hr. The mixture was combined with another batch of the crudereaction. Diluted with H₂O (30 mL) and extracted with DCM (20 mL*2). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to afford 100 mg of the title compound wasobtained as brown oil.

Step 2.(R)-3-Fluoro-3′,10′-dimethyl-1′,2′,3′,4′,9′,10′-hexahydro-7′H,11′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin]-11′-one.To a solution of tert-butyl(R)-3-fluoro-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate(80 mg, 203.84 μmol, 1 eq) in DCM (1.5 mL) was added TFA (3.50 g, 30.71mmol, 2.27 mL, 150.68 eq). The mixture was stirred at 10° C. for 1 hr.The mixture was concentrated in vacuo. The title compound (85 mg, crude,TFA) was obtained as brown oil.

Step 3.(R)—N-(3-Cyano-4-fluorophenvl)-3-fluoro-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide.To a solution of (R)-3-fluoro-3′,10‘-dimethyl-’,2′,3′, 4′,9′,10′-hexahydro-7′H,11′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin]-11′-one(80 mg, 196.86 μmol, 1 eq, TFA) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (50.44 mg, 196.86 μmol, 1 eq) inDCM (2 mL) was added TEA (99.60 mg, 984.31 μmol, 137.01 μL, 5 eq). Themixture was stirred at 15° C. for 30 min. The mixture was concentratedin vacuo. The residue was purified by prep-TLC (PE:EA=0:1), Furtherpurification by prep-HPLC (FA). The title compound (16.53 mg, 35.97μmol, 18.27% yield, 98.9% purity) was obtained as white solid. LCMS: 455[M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.82 (dd, J=2.76, 5.65 Hz, 1H),7.70 (ddd, J=2.76, 4.71, 9.10 Hz, 1H), 7.28 (t, J=8.97 Hz, 1H), 5.21(quin, J=6.21 Hz, 1H), 5.05-5.24 (m, 1H), 5.04-5.12 (m, 1H), 4.93-5.04(m, 2H), 4.41 (d, J=2.01 Hz, 2H), 4.35 (d, J=16.69 Hz, 1H), 3.44 (s,2H), 3.21 (s, 3H), 3.01 (dd, J=5.83, 15.75 Hz, 1H), 2.66 (d, J=15.81 Hz,1H), 2.42-2.62 (m, 2H), 2.22-2.36 (m, 2H), 1.23 (d, J=6.90 Hz, 3H).

Compound 143:(R)—N-(3-Cyano-4-fluorophenyl)-3,3-difluoro-3′,10′-dimethyl-11‘-oxo-1’,3′,4′, 9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide

Step 1. tert-Butyl(R)-3′,10′-dimethyl-3,11′-dioxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate.To a solution of tert-butyl(R)-3-hydroxy-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate(130 mg, 332.93 μmol, 1 eq) in DCM (2 mL) was added DMP (282.42 mg,665.86 μmol, 206.14 μL, 2 eq). The mixture was stirred at 15° C. for 1hr. The mixture was combined with another batch to dilute with DCM (30mL) and filtered, the filtrates was concentrated in vacuo. The residuewas purified by column chromatography(SiO2, PE:EA:2:1˜1:2) to give 100mg of desired product as white solid.

Step 2. tert-butyl (R)-3,3-difluoro-3′,10′-dimethyl-11′-oxo-1′3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate.To a solution of tert-butyl(R)-3′,10′-dimethyl-3,11′-dioxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate(90 mg, 231.68 μmol, 1 eq) in DCM (2 mL) was added DAST (186.72 mg, 1.16mmol, 153.05 μL, 5 eq) at −40° C. The mixture was stirred at 0° C. for 1hr. The mixture was combined with another batch (EW619-1976) to dilutewith H₂O (30 mL) and extracted with DCM (20 mL*2). The combined organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo. 100 mgcrude product was obtained as brown oil, which was used in the next stepdirectly.

Step 3. (R)-3,3-Difluoro-3′,10′-dimethyl-1′,2′,3′,4′,9′,10′-hexahydro-7′H,11′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin]-11′-one.To a solution of tert-butyl(R)-3,3-difluoro-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxylate(100 mg, 243.63 μmol, 1 eq) in DCM (2 mL) was added TFA (3.08 g, 27.01mmol, 2 mL, 110.87 eq). The mixture was stirred at 20° C. for 0.5 hr.The mixture was concentrated in vacuo to give the title compound (110mg, crude, TFA) as brown oil.

Step 4.(R)—N-(3-Cyano-4-fluorophenvl)-3,3-difluoro-3′,10′-dimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide.To a solution of(R)-3,3-Difluoro-3′,10′-dimethyl-1′,2′,3′,4′,9′,10′-hexahydro-7′H,11′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin]-11′-one(100 mg, 322.23 μmol, 1 eq, TFA) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (82.56 mg, 322.23 μmol, 1 eq) inDCM (2 mL) was added TEA (163.03 mg, 1.61 mmol, 224.25 μL, 5 eq). Themixture was stirred at 15° C. for 30 min. The residue was purified byprep-HPLC (FA). The title compound (35.85 mg, 73.15 μmol, 22.70% yield,96.4% purity) was obtained as white solid. LCMS: 473 [M+1]. ¹H NMR (400MHz, CHLOROFORM-d) 6=7.79 (dd, J=2.75, 5.44 Hz, 1H), 7.59 (ddd, J=2.87,4.52, 9.11 Hz, 1H), 7.15 (t, J 8.74 Hz, 1H), 6.69 (s, 1H), 5.14 (quin, J6.51 Hz, 1H), 4.84 (d, J 15.53 Hz, 1H), 4.41-4.52 (m, 3H), 3.46-3.58 (m,2H), 3.24 (s, 3H), 3.03 (dd, J 5.87, 16.02 Hz, 1H), 2.51-2.78 (m, 5H),1.20 (d, J 6.97 Hz, 3H).

Compound 144_E1:(S)—N-(3-Cyano-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide_E1

Step 1. 5-(tert-Butyl) 3-ethyl2-(2-(chloromethyl)allyl)-2.4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate.To a solution of 5-(tert-butyl) 3-ethyl2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (10 g,33.86 mmol, 1 eq) in DMF (130 mL) was added Cs₂CO₃ (16.55 g, 50.79 mmol,1.5 eq) and 3-chloro-2-(chloromethyl)prop-1-ene (21.16 g, 169.30 mmol,19.59 mL, 5 eq). The solution was stirred at 50° C. for 3 hr. Themixture was diluted with EtOAc (100 mL) and filtered. The filtrate waspoured into 0.5 N HCl (300 mL). The solution was extracted with ethylacetate (200 mL*2). The combined organic layers were washed with brine(200 mL*3), dried with anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography. The title compound (5.3g, 13.53 mmol, 39.96% yield, 98% purity) was obtained as white solid.LCMS: 384 [M+1].

Step 2. tert-Butyl10-methyl-8-methylene-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a solution of 5-(tert-butyl) 3-ethyl2-(2-(chloromethyl)allyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate(5.3 g, 13.81 mmol, 1 eq) in EtOH (21 mL) was added MeNH₂ (42.88 g,414.20 mmol, 30 eq, 30% MeNH₂ in EtOH). The mixture was heated to 80° C.for 16 hr in a sealed tube. The solution was concentrated. The residuewas purified by column chromatography. The title compound (2.6 g, 7.82mmol, 56.65% yield) was obtained as white solid. LCMS: 333 [M+1].

Step 3. tert-Butyl10-methyl-8,11-dioxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a solution of tert-butyl10-methyl-8-methylene-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(1.2 g, 3.61 mmol, 1 eq) in THF (30 mL) and H₂O (15 mL) was added OsO₄(275.34 mg, 1.08 mmol, 56.19 μL, 0.3 eq) and NaIO₄ (2.32 g, 10.83 mmol,600.14 μL, 3 eq) at 0° C. The mixture was stirred at 10° C. for 7 hr.The solution was poured into ice sat. NaHSO₃ (100 mL). The mixtureextracted with ethyl acetate (50 mL*2). The combined organic layers werewashed with brine (50 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography. Thetitle compound (580 mg, 1.56 mmol, 43.21% yield, 90% purity) wasobtained as white solid. LCMS: 353 [M+19].

Step 4. tert-Butyl8-hydroxy-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.To a solution of tert-butyl10-methyl-8,11-dioxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(580 mg, 1.56 mmol, 1 eq) in MeOH (15 mL) was added NaBH₄ (107.62 mg,2.84 mmol, 1.82 eq) at 0° C. The solution was stirred at 0° C. for 1 hr.The solution was poured into water (30 mL). The mixture extracted withethyl acetate (20 mL*2). The combined organic layers were washed withbrine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated.The title compound (550 mg, crude) was obtained as white solid. LCMS:337 [M+1].

Step 5. tert-Butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E1and tert-butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E2.Racemate of tert-butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(580 mg, 1.53 mmol) was resolved via SFC to give both enantiomers:tert-Butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E1(200 mg, 558.29 μmol, 36.38% yield, 93.9% purity, t=3.176 min) andtert-Butyl8-hydroxy-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E2(250 mg, 684.48 mol, 44.60% yield, 92.1% purity, t=3.401 min) as whitesolid. SFC analytical method: IC-3S_4_5_40_3 ML Column: Chiralpak IC-3100×4.6 mm I.D., 3 um Mobile phase:iso-propanol (0.05% DEA) in CO₂ from5% to 40% Flow rate: 3 mL/min Wavelength:254 nm.

SFC separation method: column: IC(250 mm*30 mm, 10 um); mobile phase:[0.1% NH₃H₂O IPA]; B %: 35%-35%, 4.35 min; 100 min.

Step 6. tert-Butyl(S)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E1.To a solution of tert-Butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E1(140.00 mg, 390.80 μmol, 1 eq) in DCM (2 mL) was added DAST (201.26 mg,1.25 mmol, 164.97 μL, 3.19 eq) at −20° C. The solution was stirred at 0°C. for 0.5 hr. The solution was poured into ice sat.NaHCO₃ (30 mL). Themixture extracted with ethyl acetate (20 mL*2). The combined organiclayers were washed with brine (20 mL), dried with anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by prep-TLC. Thetitle compound (75 mg, 221.65 μmol, 56.72% yield) was obtained as yellowoil.

Step 7.(S)-8-Fluoro-10-methyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_E1.To a solution of tert-butyl(S)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E1(75.00 mg, 221.65 μmol, 1 eq) in DCM (5 mL) was added TFA (7.70 g, 67.53mmol, 5.00 mL, 304.68 eq). The solution was stirred at 25° C. for 0.5hr. The solution was concentrated. The title compound (80 mg, crude,TFA) was obtained as yellow oil.

Step 8.(S)—N-(3-Cyano-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamideE1. To a solution of(S)-8-fluoro-10-methyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one_E1(78 mg, 1 eq, TFA) in DCM (5 mL) was added TEA (112.02 mg, 1.11 mmol,154.09 μL, 5 eq) and phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (56.73mg, 221.40 μmol, 1 eq). The solution was stirred at 25° C. for 16 hr.The solution was concentrated. The residue was purified by prep-HPLC.The title compound (52.09 mg, 129.06 μmol, 99.2% purity) was obtained aswhite solid. LCMS: 401 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.79 (dd,J=2.76, 5.52 Hz, 1H), 7.59 (ddd, J=2.76, 4.52, 9.03 Hz, 1H), 7.14 (t,J=8.66 Hz, 1H), 6.78 (s, 1H), 4.65-4.86 (m, 2H), 4.35-4.63 (m, 1H),3.97-4.07 (m, 1H), 3.79-3.95 (m, 2H), 3.22 (s, 3H), 2.88 (br t, J=5.71Hz, 2H).

Compound 144_E2:(R)—N-(3-Cyano-4-fluorophenvl)-8-fluoro-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamideE2

The title compound was prepared in a manner analogous to Compound 144_E1substituting tert-Butyl8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E2for tert-butyl8-hydroxy-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E1.LCMS: 401 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.78 (dd, J=2.76, 5.27Hz, 1H), 7.56-7.63 (m, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.81 (s, 1H),4.65-4.89 (m, 2H), 4.32-4.62 (m, 4H), 4.01 (br dd, J=5.21, 10.85 Hz,1H), 3.77-3.95 (m, 2H), 3.22 (s, 3H), 2.82-2.94 (m, 2H).

Compound 145_D1:(R)—N-(3-Cyano-4-fluorophenvl)-8-(2,2-difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1. tert-Butyl(R)-8-(2,2-difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate

To a suspension of NaH (24.97 mg, 624.28 μmol, 60% purity, 3 eq) in THF(0.6 mL) was added a solution of tert-butyl(R)-8-hydroxy-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate_E1(70 mg, 208.09 μmol, 1 eq) in THF (0.6 mL) at −40° C., the mixture wasstirred at −40° C. for 30 min. Then a solution of 2,2-difluoroethyltrifluoromethanesulfonate (133.67 mg, 624.28 μmol, 3 eq) in THE (0.4 mL)was added at −40° C. dropwise. The mixture was stirred at 5° C. for 1hr. The mixture was quenched with H₂O (20 mL) at 0° C. and extractedwith EA (30 mL*2). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (85 mg,crude) as yellow oil, which was used in the next step directly.

Step 2.(R)-8-(2,2-Difluoroethoxy)-10-methyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one.To a solution of tert-butyl(R)-8-(2,2-difluoroethoxy)-10-methyl-1-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(120 mg, 299.69 μmol, 1 eq) in DCM (2 mL) was added TFA (3.08 g, 27.01mmol, 2.00 mL, 90.13 eq). The mixture was stirred at 15° C. for 0.5 hr.The mixture was concentrated in vacuo to give the title compound (126mg, crude, TFA) as yellow oil.

Step 3.(R)—N-(3-Cyano-4-fluorophenyl)-8-(2,2-difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(R)-8-(2,2-difluoroethoxy)-10-methyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(125 mg, 301.69 μmol, 1 eq, TFA) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (77.30 mg, 301.69 μmol, 1 eq) inDCM (5 mL) was added TEA (152.64 mg, 1.51 mmol, 209.96 μL, 5 eq). Themixture was stirred at 15° C. for 3 hr. The mixture was concentrated invacuo. The residue was purified by prep-HPLC(FA) to give the titlecompound (65.88 mg, 140.76 μmol, 46.66% yield, 98.8% purity) wasobtained a white solid. LCMS: 463 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d)6=7.78 (dd, J=2.76, 5.40 Hz, 1H), 7.60 (ddd, J=2.82, 4.55, 9.07 Hz, 1H),7.15 (t, J=8.72 Hz, 1H), 6.79 (s, 1H), 5.75-6.08 (m, 1H), 4.57-4.78 (m,3H), 4.25-4.35 (m, 2H), 3.73-3.95 (m, 4H), 3.42-3.60 (m, 2H), 3.22 (s,3H), 2.79-2.92 (m, 2H).

Compound 145_D2:(S)—N-(3-Cyano-4-fluorophenyl)-8-(2,2-difluoroethoxy)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

The title compound was prepared in a manner analogous to Compound 145_D1substituting tert-butyl(S)-8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylatefor tert-butyl(R)-8-hydroxy-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate.LCMS: 463 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 6=7.78 (dd, J=2.76, 5.52Hz, 1H), 7.60 (ddd, J=2.76, 4.58, 9.10 Hz, 1H), 7.14 (t, J=8.72 Hz, 1H),6.84 (s, 1H), 5.75-6.10 (m, 1H), 4.55-4.77 (m, 3H), 4.25-4.36 (m, 2H),3.72-3.95 (m, 4H), 3.43-3.61 (m, 2H), 3.22 (s, 3H), 2.79-2.93 (m, 2H).

Compound 146:(R)—N-(3-Cyano-4-fluorophenyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

Step 1.(R)-3-Methyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one.To a solution of tert-butyl(R)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(140 mg, 436.97 μmol, 1 eq) in DCM (10 mL) was added TFA (7.70 g, 67.53mmol, 5 mL, 154.54 eq). The solution was stirred at 20° C. for 1 hr. TLC(ethyl acetate) indicated starting material was consumed completely. Thesolution was concentrated. The title compound (146 mg, crude, TFA) wasobtained as yellow oil.

Step 2.(R)—N-(3-Cyano-4-fluorophenvl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.To a solution of(R)-3-methyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(73 mg, 218.37 μmol, 1 eq, TFA) in DCM (5 mL) was added TEA (66.29 mg,655.11 μmol, 91.18 μL, 3 eq) and phenylN-(3-cyano-4-fluoro-phenyl)carbamate (50.36 mg, 196.53 μmol, 0.9 eq).The solution was stirred at 20° C. for 16 hr. The solution wasconcentrated. The residue was purified by prep-HPLC(FA). The titlecompound (55 mg, 143.11 μmol, 65.54% yield, 99.5% purity) was obtainedas a white solid. LCMS: 383 [M+1]. H NMR (400 MHz, CHLOROFORM-d) δ 7.81(dd, J=2.76, 5.52 Hz, 1H), 7.63 (ddd, J=2.89, 4.55, 9.13 Hz, 1H), 7.12(t, J=8.78 Hz, 1H), 7.02 (s, 1H), 6.20 (br s, 1H), 5.15 (quin, J=6.40Hz, 1H), 4.88 (d, J=15.94 Hz, 1H), 4.42-4.55 (m, 3H), 3.43-3.53 (m, 2H),3.02 (dd, J=5.83, 15.75 Hz, 1H), 2.67 (d, J=15.81 Hz, 1H), 2.27-2.38 (m,2H), 1.17 (d, J=6.90 Hz, 3H).

Compound 147:(R)—N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

To a solution of(R)-3-methyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(73 mg, 218.37 μmol, 1 eq, TFA) in DCM (5 mL) was added TEA (66.29 mg,655.11 μmol, 91.18 μL, 3 eq) and phenylN-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (58.81 mg, 196.53 μmol,0.9 eq). The solution was stirred at 20° C. for 16 hr. The solution wasconcentrated. The residue was purified by prep-HPLC(FA). The titlecompound (47.8 mg, 112.02 μmol, 51.30% yield, 99.69% purity) wasobtained as white solid. LCMS: 426 [M+1]. 1H NMR (400 MHz, CHLOROFORM-d)δ 7.71 (dd, J=2.70, 6.09 Hz, 1H), 7.55-7.64 (m, 1H), 7.12 (t, J=9.47 Hz,1H), 6.87 (s, 1H), 6.12 (br s, 1H), 5.17 (quin, J=6.40 Hz, 1H), 4.88 (d,J=15.81 Hz, 1H), 4.43-4.56 (m, 3H), 3.45-3.53 (m, 2H), 3.03 (dd, J=5.90,15.81 Hz, 1H), 2.67 (d, J=15.81 Hz, 1H), 2.28-2.39 (m, 2H), 1.17 (d,J=6.90 Hz, 3H).

Compound 148:(3R,8S)—N-(3-Cyano-4-fluorophenyl)-8-(hydroxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide

Step 1. (2S)-1-allyloxy-3-[tert-butyl (dimethyl)silyl]oxy-propan-2-ol.To a solution of (2R)-3-allyloxypropane-1, 2-diol (8 g, 60.53 mmol, 1eq) and Imid (6.18 g, 90.80 mmol, 1.5 eq) in DCM (50 mL) was added TBSCl(9.12 g, 60.53 mmol, 7.42 mL, 1 eq) dropwise at 0° C. with stirring for1 h. The mixture was quenched with aqueous saturated NH₄Cl solution (50mL*1) and extracted with EtOAc (50 mL*3). The organic layers were washedwith brine (50 mL*1), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=50/1 to 20/1). Thetitle compound (12 g, 48.70 mmol, 80.45% yield) was obtained ascolorless liquid.

Step 2. [(1S)-1-(Allyloxymethyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]methanesulfonate. To a solution of(2S)-1-allyloxy-3-[tert-butyl(dimethyl)silyl]oxy-propan-2-ol (12 g,48.70 mmol, 1 eq) and DIEA (18.88 g, 146.09 mmol, 25.45 mL, 3 eq) in DCM(80 mL) was added MsCl (8.37 g, 73.05 mmol, 5.65 mL, 1.5 eq) at 0° C.with stirring for 2 h. The mixture was quenched with aqueous 1 N HClsolution (100 mL*1) and extracted with EtOAc (60 mL*3). The organiclayers were washed with brine (60 mL*1), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuum to afford the title compound (15.9g, crude) was obtained as yellow oil, which was directly used in thenext step without purification.

Step 3. (2R)-1-Allyloxy-3-[tert-butyl (dimethyl) silyl]oxy-N-methyl-propan-2-amine. A mixture of[(1S)-1-(allyloxymethyl)-2-[tert-butyl (dimethyl) silyl] oxy-ethyl]methanesulfonate (15.9 g, 49.00 mmol, 1 eq) and methanamine (49.00 mmol,30%, 50 mL EtOH solution) was stirred at 80° C. for 32 h. Then themixture was stirred at 80° C. for another 16 h. The mixture wasconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=50/1 to 10/1) togive the title compound (8.0 g, 30.83 mmol, 62.93% yield) as yellow oil.

Step 4. tert-Butyl (6R)-3-[[(1R)-1-(allyloxymethyl)-2-[tert-butyl(dimethyl) silyl]oxy-ethyl]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate.To a solution of(6R)-5-tert-butoxycarbonyl-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylicacid (2 g, 7.11 mmol, 1 eq) and(2R)-1-allyloxy-3-[tert-butyl(dimethyl)silyl]oxy-N-methyl-propan-2-amine(2.21 g, 8.53 mmol, 1.2 eq) in Py (15 mL) was added EDCI (1.64 g, 8.53mmol, 1.2 eq). The solution was stirred at 40° C. for 16 hr. Thesolution was diluted with ethyl acetate (100 mL). The organic phase waswashed with 1N HCl (100 mL*3) and brine (80 mL), dried with anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography to give the title compound (1.9 g, 3.63 mmol, 51.12%yield) as yellow solid. LCMS: 523 [M+1].

Step 5. tert-Butyl(6R)-3-[[(1S)-1-(allyloxymethyl)-2-hydroxy-ethyl]-methyl-carbamoyl]-6-methyl-2,4, 6, 7-tetrahydropyrazolo [4, 3-c] pyridine-5-carboxylate. To asolution of tert-butyl(6R)-3-[[(1R)-1-(allyloxymethyl)-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(1.9 g, 3.63 mmol, 1 eq) in THF (30 mL) was added TBAF (1 M, 4.36 mL,1.2 eq). The solution was stirred at 25° C. for 0.5 hr. The solution waspoured into water (30 mL). The mixture extracted with ethyl acetate (20mL*2). The combined organic layers were washed with brine (20 mL*3),dried with anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography to give the title compound (1.23 g,3.01 mmol, 82.84% yield) as white solid.

Step 6. tert-Butyl(3R,8S)-8-(allyloxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate.To a solution of tert-butyl(6R)-3-[[(1S)-1-(allyloxymethyl)-2-hydroxy-ethyl]-methyl-carbamoyl]-6-methyl-2,4, 6, 7-tetrahydropyrazolo [4, 3-c] pyridine-5-carboxylate (1.13 g, 2.77mmol, 1 eq) in THF (60 mL) was added tributylphosphane (1.68 g, 8.30mmol, 2.05 mL, 3 eq). The solution was stirred at 25° C. for 15 min.Then ADDP (2.09 g, 8.30 mmol, 3 eq) was added. The solution was stirredat 70° C. for 16 hr. The solution was diluted with ethyl acetate (50mL). The organic phase was washed with 1N HCl (30 mL*3) and brine (50mL), dried with anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatography to give the title compound (818mg, 2.07 mmol, 74.97% yield, 99% purity) as white solid. LCMS: 391[M+1].

Step 7. give tert-Butyl(3R,8S)-8-(hydroxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate.A solution of tert-butyl(3R,8S)-8-(allyloxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate(900 mg, 2.30 mmol, 1 eq), OSO₄ (175.79 mg, 691.46 μmol, 35.88 μL, 0.3eq), NaIO₄ (2.46 g, 11.52 mmol, 638.59 μL, 5 eq), and NMO (1.35 g, 11.52mmol, 1.22 mL, 5 eq) in dioxane (30 mL) and H₂O (10 mL) was stirred at60° C. for 16 hr. The mixture was poured into water (30 mL). Thesolution was extracted with EtOAc (30 mL*2). The combined organic layerswere washed with Na₂S₂O₃ (30 mL) and brine (30 mL), dried with anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography to give the desired product (600 mg, 1.67 mmol, 72.43%yield, 97.5% purity) as white solid, which was 86% de from SFC. Theproduct was re-purified by SFC (Analysis condition: OJ-3S_3_5_40_3 ML;Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 um Mobile phase: methanol(0.05% DEA) in CO₂ from 5% to 40% Flow). Separation condition: Column:OJ (250 mm*30 mm, 5 um); mobile phase: [0.1% NH₃H₂O MeOH]; B %: 15%-15%,1.8 min; 90 min) to give tert-butyl(3R,8S)-8-(hydroxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate(410 mg, 1.17 mmol, 68.33% yield) was obtained as white solid. LCMS: 351[M+1].

Step 8.(3R,8S)-8-(hydroxymethyl)-3,9-dimethyl-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-c]pyrazin-10-one. To a solution of tert-butyl(3R,8S)-8-(hydroxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate(40 mg, 107.30 μmol, 1 eq) in DCM (5 mL) was added TFA (7.70 g, 67.53mmol, 5 mL, 629.35 eq). The solution was stirred at 20° C. for 0.5 hr.The solution was concentrated to afford the title compound (40 mg,crude, TFA) was obtained as yellow oil.

Step 9.(3R,8S)—N-(3-Cyano-4-fluorophenvl)-8-(hydroxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide.To a solution of(3R,8S)-8-(hydroxymethyl)-3,9-dimethyl-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-c]pyrazin-10-one(39 mg, 1 eq, TFA) in DCM (6 mL) was added TEA (45.98 mg, 454.39 μmol,63.25 μL, 5 eq) and phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (20.96mg, 81.80 μmol, 0.9 eq). The solution was stirred at 20° C. for 16 hr.The solution was concentrated. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water(0.225% FA)-ACN]; B %: 18%-48%, 10.5 min). The title compound (27.27 mg,65.40 μmol, 98.9% purity) was obtained as white solid. LCMS: 413 [M+1].¹H NMR (400 MHz, CHLOROFORM-d) δ 7.82 (ddd, J=2.76, 4.58, 9.10 Hz, 1H),7.66 (dd, J=2.64, 5.40 Hz, 1H), 7.18 (t, J=8.78 Hz, 1H), 6.89 (s, 1H),4.99-5.14 (m, 1H), 4.45-4.54 (m, 1H), 4.31-4.41 (m, 1H), 4.03-4.26 (m,3H), 3.74-3.89 (m, 2H), 3.26 (s, 3H), 2.89 (dd, J=5.65, 15.69 Hz, 1H),2.61 (d, J=15.81 Hz, 1H), 1.04 (d, J=6.90 Hz, 3H).

Compound 149:(3R,8S)—N-(3-cyano-4-fluorophenvl)-8-(fluoromethyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide

Step 1. tert-Butyl(3R,8S)-8-(fluoromethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate.To a solution of tert-butyl(3R,8S)-8-(hydroxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate(120 mg, 342.45 μmol, 1 eq) in DCM (6 mL) was added DAST (165.60 mg,1.03 mmol, 135.74 μL, 3 eq) at 0° C. The solution was stirred at 20° C.for 0.5 hr. The solution was poured into sat. NaHCO₃ (30 mL). Themixture extracted with ethyl acetate (20 mL*2). The combined organiclayers were washed with brine (20 mL), dried with anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by prep-TLC (SiO₂,Ethyl acetate, Rf=0.51) to give the title compound (75 mg, 212.82 μmol,49.72% yield) as white solid.

Step 2.(3R,8S)-8-(Fluoromethyl)-3,9-dimethyl-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-c]pyrazin-10-one.To a solution of tert-butyl(3R,8S)-8-(fluoromethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate(70 mg, 198.64 μmol, 1 eq) in DCM (5 mL) was added TFA (7.70 g, 67.53mmol, 5 mL, 339.97 eq). The solution was stirred at 25° C. for 0.5 hr.The solution was concentrated to give the title compound (73 mg, crude,TFA) as yellow oil.

Step 3.(3R,8S)—N-(3-cyano-4-fluorophenyl)-8-(fluoromethyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide.To a solution of(3R,8S)-8-(fluoromethyl)-3,9-dimethyl-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-c]pyrazin-10-one(73 mg, 289.35 μmol, 1 eq) in DCM (5 mL) was added phenylN-(3-cyano-4-fluoro-phenyl)carbamate (74.14 mg, 289.35 μmol, 1 eq) andTEA (146.40 mg, 1.45 mmol, 201.37 μL, 5 eq). The solution was stirred at25° C. for 16 hr. LC—The mixture was concentrated and purified byprep-HPLC to give the title compound (46.27 mg, 111.03 μmol, 38.37%yield, 99.44% purity) as white solid. LCMS: 415 [M+1].

1H NMR (400 MHz, CHLOROFORM-d) δ 7.79 (dd, J=2.69, 5.38 Hz, 1H), 7.62(m, 1H), 7.13 (t, J=8.74 Hz, 1H), 6.97 (s, 1H), 5.15 (m, 1H), 4.87 (d,J=15.77 Hz, 1H), 4.33-4.62 (m, 5H), 3.94-4.09 (m, 1H), 3.17-3.29 (m,3H), 3.03 (dd, J=5.69, 15.96 Hz, 1H), 2.70 (d, J=16.02 Hz, 1H), 1.17 (d,J=6.97 Hz, 3H).

Compound 150:(3R,8S)—N-(3-cyano-4-fluorophenyl)-8-((2,2-difluoroethoxy)methyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide

Step 1. tert-Butyl(3R,8S)-8-(2,2-difluoromethoxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate.To a solution of tert-butyl(3R,8S)-8-(hydroxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate(100 mg, 285.38 μmol, 1 eq) in THE (2 mL) was added NaH (22.83 mg,570.76 μmol, 60% purity, 2 eq) at −20° C. The solution was stirred at−20° C. for 30 min. Then 2,2,2-difluoroethyl trifluoromethanesulfonate(183.31 mg, 856.13 μmol, 3 eq) was added, the solution was stirred at25° C. for 2 hr. The solution was poured into water (30 mL). The mixtureextracted with ethyl acetate (20 mL*2). The combined organic layers werewashed with brine (20 mL*3), dried with anhydrous Na₂SO₄, filtered andconcentrated to give the title compound (120 mg, crude) as yellow oil.

Step 2.(3R,8S)-8-(2,2-Difluoromethoxymethyl)-3,9-dimethyl-1,2,3,4,7,8-hexahydropyrido[2.3]pyrazolo[2,4-c]pyrazin-10-one.To a solution of tert-butyl(3R,8S)-8-(2,2-difluoromethoxymethyl)-3,9-dimethyl-10-oxo-3,4,7,8-tetrahydro-1H-pyrido[2,3]pyrazolo[2,4-c]pyrazine-2-carboxylate(110 mg, 265.41 μmol, 1 eq) in DCM (5 mL) was added TFA (7.70 g, 67.53mmol, 5 mL, 254.43 eq). The solution was stirred at 25° C. for 0.5 hr.The solution was concentrated to afford the title compound (120 mg,crude, TFA) as yellow oil.

Step 3.(3R,8S)—N-(3-Cyano-4-fluorophenyl)-8-((2,2-difluoroethoxy)methyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide.To a solution of(3R,8S)-8-(2,2-difluoromethoxymethyl)-3,9-dimethyl-1,2,3,4,7,8-hexahydropyrido[2,3]pyrazolo[2,4-c]pyrazin-10-one(110 mg, 349.95 μmol, 1 eq) in DCM (5 mL) was added phenylN-(3-cyano-4-fluoro-phenyl)carbamate (89.67 mg, 349.95 μmol, 1 eq) andTEA (106.23 mg, 1.05 mmol, 146.13 μL, 3 eq). The solution was stirred at25° C. for 16 hr. The solution was concentrated. The residue waspurified by prep-HPLC to give the title compound (80.53 mg, 165.22 μmol,47.21% yield, 97.75% purity) as a white solid. LCMS: 477 [M+1]. ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.80 (dd, J=2.51, 5.14 Hz, 1H), 7.54-7.69 (m,1H), 7.13 (t, J=8.66 Hz, 1H), 6.87 (s, 1H), 5.60-6.01 (m, 1H), 5.15 (brt, J=6.21 Hz, 1H), 4.85 (br d, J=15.56 Hz, 1H), 4.49-4.65 (m, 2H),4.33-4.47 (m, 1H), 3.83-3.99 (m, 1H), 3.46-3.80 (m, 4H), 3.19 (s, 3H),3.03 (br dd, J=5.52, 15.81 Hz, 1H), 2.71 (br d, J=16.06 Hz, 1H), 1.18(br d, J=6.90 Hz, 3H).

Compound 151:((3R,8S)-3,10-Dimethyl-2-(4-nitrobenzoyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-8-yl)methyl4-nitrobenzoate

Step 1.(3R,8S)-8-(hydroxymethyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one.A mixture of tert-butyl(3R,8S)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxylate(100.00 mg, 274.39 μmol, 1 eq) and TFA (3.08 g, 27.01 mmol, 2.00 mL,98.44 eq) in DCM (4 mL) was stirred at 15° C. for 1 hr under N₂atmosphere. The mixture was concentrated in vacuum to give the titlecompound (103.8 mg, 274.35 μmol, 99.98% yield, TFA) as a yellow oil,which was used directly for next step.

Step 2.((3R,8S)-3,10-Dimethyl-2-(4-nitrobenzoyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-8-yl)methyl4-nitrobenzoate. A mixture of((3R,8S)-8-(hydroxymethyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(103 mg, 272.24 μmol, 1 eq, TFA), 4-nitrobenzoyl chloride (325.33 mg,1.75 mmol, 6.44 eq) and TEA (220.38 mg, 2.18 mmol, 303.14 μL, 8 eq) inDCM (6 mL) was stirred at 15° C. for 16 hr under N2 atmosphere. MeOH (6mL) was added to the mixture and stirred for 30 min. The mixture waswashed by cool Na₂CO₃ (aq. 1N, 20 mL*3). The organic phase was driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum to give titlecompound (180 mg, crude) as a yellow oil.

A mixture of resulting((3R,8S)-8-(hydroxymethyl)-3,10-dimethyl-1,2,3,4,7,8,9,10-octahydro-11H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-11-one(180.00 mg, crude), and 4-nitrobenzoyl chloride (80.79 mg, 435.39 μmol,1 eq), TEA (88.11 mg, 870.77 μmol, 121.20 μL, 2 eq), DMAP (2.66 mg,21.77 μmol, 0.05 eq) in DCM (5 mL) was degassed and purged with N₂ for 3times, and then the mixture was stirred at 15° C. for 16 hr under N2atmosphere. LCMS showed the desired product was form mainly. The mixturewas poured into ice-water (10 mL) and stirred for 1 min. The aqueousphase was extracted with DCM (20 mL). The combined organic phase waswashed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by prep-HPLC to givethe title compound (85 mg, 146.57 μmol, 33.66% yield, 97% purity) as awhite solid. LCMS: 563 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.32 (brd, J=8.78 Hz, 4H), 8.19 (d, J=8.78 Hz, 2H), 7.60 (d, J=8.78 Hz, 2H),5.43-5.71 (m, 1H), 4.15-4.59 (m, 6H), 2.94-3.53 (m, 7H), 2.56-2.82 (m,1H), 1.23-1.35 (m, 3H).

Example 1: HBV Assembly Assay

The interference of compounds from this invention with HBV capsidassembly could be measured using an in vitro assembly assay based onfluorescence quenching, which was developed according to a methoddescribed by Zlotnick and coworkers (Nature Biotechnology 2006, 24:358).Ina typical assay, a mutant HBV C150 protein (amino acids 1-150, C49A,C61A, C107A, 150C) is cloned into a T7 RNA-polymerase based expressionvector, expressed in E. coli and purified to homogeneity as a dimer. Thepurified HBV core protein is desalted and labeled with BODIPY-FL Dye.

In a non-limiting embodiment, the assembly assay is conducted in 96-wellplate format. The assembly reactions are carried out in 50 mM Hepesbuffer, pH 7.5 and 150 mM NaCl. The compounds are pre-incubated with theHBV CA protein for 15 min, and the assembly reactions are initiated byaddition of NaCl. The reaction is allowed to continue for 1 hour at roomtemperature. The changes in fluorescence between DMSO treated andcompound treated samples are recorded and analyzed for assemblymodulation.

Example 2: HBV Replication Inhibition Assay

HBV replication inhibition by the disclosed compounds were determined incells infected or transfected with HBV, or cells with stably integratedHBV, such as HepG2.2.15 cells (Sells et al. 1987). In this example,HepG2.2.15 cells were maintained in cell culture medium containing 10%fetal bovine serum (FBS), Geneticin, L-glutamine, penicillin andstreptomycin. HepG2.2.15 cells were seeded in 96-well plates at adensity of 40,000 cells/well and were treated with serially dilutedcompounds at a final DMSO concentration of 0.5% either alone or incombination by adding drugs in a checker box format. Cells wereincubated with compounds for three days, after which medium was removedand fresh medium containing compounds was added to cells and incubatedfor another three days. At day 6, supernatant was removed and treatedwith DNase at 37° C. for 60 minutes, followed by enzyme inactivation at75° C. for 15 minutes.

Encapsidated HBV DNA was released from the virions and covalently linkedHBV polymerase by incubating in lysis buffer (Affymetrix QS0010)containing 2.5 μg proteinase K at 50° C. for 40 minutes. HBV DNA wasdenatured by addition of 0.2 M NaOH and detected using a branched DNA(BDNA) QuantiGene assay kit according to manufacturer recommendation(Affymetrix). HBV DNA levels were also quantified using qPCR, based onamplification of encapsidated HBV DNA extraction with QuickExtractionSolution (Epicentre Biotechnologies) and amplification of HBV DNA usingHBV specific PCR probes that can hybridize to HBV DNA and afluorescently labeled probe for quantitation. In addition, cellviability of HepG2.2.15 cells incubated with test compounds alone or incombination was determined by using CellTitre-Glo reagent according tothe manufacturer protocol (Promega). The mean background signal fromwells containing only culture medium was subtracted from all othersamples, and percent inhibition at each compound concentration wascalculated by normalizing to signals from HepG2.2.15 cells treated with0.5% DMSO using equation E1.

% inhibition=(DMSOave−Xi)/DMSOave×100%  E1:

where DMSOave is the mean signal calculated from the wells that weretreated with DMSO control (0% inhibition control) and Xi is the signalmeasured from the individual wells. EC50 values, effectiveconcentrations that achieved 50% inhibitory effect, were determined bynon-linear fitting using Graphpad Prism software (San Diego, Calif.) andequation E2:

Y=Ymin+(Ymax−Ymin)/(1+10(LogEC50−X)×HillSlope)  E2:

where Y represents percent inhibition values and X represents thelogarithm of compound concentrations.

Selected disclosed compounds were assayed in the HBV replication assay(BDNA assay), as described above and a representative group of theseactive compounds is shown in Table 6. Table 6 shows EC₅₀ values obtainedby the BDNA assay for a group of select compounds. In Table 6, “A”represents 1<EC₅₀≤100; “B” represents 100<EC₅₀≤500; “C” represents500<EC₅₀≤1000; and “D” represents EC₅₀>1000.

TABLE 6 Activity in BDNA-assay (EC₅₀) DNA Compound EC₅₀ ID Compound Name(nM) 001 N-(3-chloro-4-fluorophenyl)-10-methyl-8-methylene-11- Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 002N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 003N-(3-chloro-4-fluorophenyl)-8-hydroxy-8- C(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 004N-(3-chloro-4-fluorophenyl)-8-hydroxy-10-methyl-11- Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′,3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 005N-(3-chloro-4-fluorophenyl)-8,8-difluoro-10-methyl-11- Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 006N-(3-chloro-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo- A1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 007N-(3-bromo-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo- A1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 008N-(2-bromo-3-fluoropyridin-4-yl)-8-fluoro-10-methyl-11- Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 009N-(3-cyano-4-fluorophenyl)-8-fluoro-10-methyl-11-oxo- A1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 0108-fluoro-N-(4-fluoro-3-methylphenyl)-10-methyl-11-oxo- A1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 0118-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 012N-(5-chloro-2,4-difluorophenyl)-8-fluoro-10-methyl-11- Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 013N-(5-bromo-2,4-difluorophenyl)-8-fluoro-10-methyl-11- Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 014N-(3-chloro-4-fluoro-phenyl)-8,10-dimethyl-11-oxo- A1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide 015N-(3-chloro-4-fluoro-phenyl)-10-methyl-11-oxo- A1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide 016A(S*)-N-(3-chloro-4-fluorophenyl)-8-methoxy-10-methyl- A11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 016B(R*)-N-(3-chloro-4-fluorophenyl)-8-methoxy-10-methyl- A11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 017N-(3-chloro-4-fluorophenyl)-8-ethoxy-10-methyl-11-oxo- A1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 018N-(3-chloro-4-fluorophenyl)-8-(2,2-difluoroethoxy)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 0198-amino-N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo- B1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 020N-(3-chloro-4-fluorophenyl)-8-(dimethylamino)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′.3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 021N-(3-chloro-4-fluorophenyl)-10-methyl-8-morpholino-11- Boxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 022N-(3-chloro-4-fluorophenyl)-8-(3,3-difluoroazetidin-1- Byl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 0238-(azetidin-1-yl)-N-(3-chloro-4-fluorophenyl)-10-methyl- A11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 024N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-8- A(pyrrolidin-1-yl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 025N-(3-chloro-4-fluorophenyl)-10-methyl-8-(methylthio)- A11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 026AN-(3-chloro-4-fluorophenyl)-10-methyl-8- D(methylsulfinyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 026BN-(3-chloro-4-fluorophenyl)-10-methyl-8- C(methylsulfinyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 027N-(3-chloro-4-fluoro-phenyl)-10-methyl-8- Amethylsulfonyl-11-oxo-1,3,4,7,8,9-hexahydropyrido[2,3]pyrazolo[2,4-b][1,4]diazepine-2-carboxamide 028 methyl2-(2-((3-chloro-4-fluorophenyl)carbamoyl)-10- Bmethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepin-8-yl)acetate 029N-(3-chloro-4-fluorophenyl)-8-(2-hydroxyethyl)-10- Bmethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 030 ethyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl- D11-oxo-2,3,4,7,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8-carboxylate 031N2-(3-chloro-4-fluorophenyl)-N8,10-dimethyl-11-oxo- A1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,8-dicarboxamide 032N2-(3-chloro-4-fluorophenyl)-N8,N8,10-trimethyl-11- Boxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,8-dicarboxamide 033N-(3-chloro-4-fluorophenyl)-8-(2-hydroxypropan-2-yl)- A10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 034N-(3-chloro-4-fluorophenyl)-8-(1-hydroxyethyl)-10- Bmethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 035N-(3-chloro-4-fluorophenyl)-8-(1-hydroxypropyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 036N-(3-chloro-4-fluorophenyl)-8-(cyclopropyl A(hydroxy)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 037N-(3-chloro-4-fluorophenyl)-8-(difluoromethyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 038N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)-11- Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 039N-(3-chloro-4-fluorophenyl)-9,10-dimethyl-11-oxo- A1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 040 methyl2-((3-chloro-4-fluorophenyl)carbamoyl)-9-methyl- B10-oxo-1,2,3,4,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8-carboxylate 041N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-9- Amethyl-10-oxo-3,4,9,10-tetrahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide 0422-((3-chloro-4-fluorophenyl)carbamoyl)-9-methyl-10- Doxo-1,2,3,4,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8-carboxylic acid 043 methyl2-((3-chloro-4-fluorophenyl)carbamoyl)-9-methyl- B10-oxo-1,2,3,4,7,8,9,10-octahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-8-carboxylate 044N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-9- Amethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide 045N-(3-chloro-4-fluorophenyl)-9-methyl-10-oxo- A3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide 046N-(3-chloro-4-fluorophenyl)-10-methyl-1,3,4,7,8,9,10,11- Doctahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 047N-(3-chloro-4-fluorophenyl)-8-(2-cyclopropyl-1- Ahydroxyethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 048(3R)-N-(3-chloro-4-fluorophenyl)-10-(2-hydroxy-2- Bmethylpropyl)-3-methyl-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 049(3R)-N-(3-chloro-4-fluorophenyl)-10-(2-hydroxyethyl)- A3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 050N-(3-chloro-4-fluorophenyl)-10-methyl-8-(methylamino)- B11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 051N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-11-oxo- A10-(2,2,2-trifluoroethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 052 ethyl2-(3-chloro-4-fluorophenyl)carbamoyl)-8,10- Bdimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-8- carboxylate 053N-(3-chloro-4-fluorophenyl)-8-(hydroxymethyl)-8,10- Adimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 054N-(3-chloro-4-fluorophenyl)-8-(3,3-difluoropyrrolidin-1- Byl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 055N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-8- B(piperidin-l-yl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 056N-(3-chloro-4-fluorophenyl)-8-(4,4-difluoropiperidin-1- Byl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 057 methyl2-((3-chloro-4-fluorophenyl)carbamoyl)-10- Bmethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9- carboxylate 0582-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11- Doxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylic acid 059N2-(3-chloro-4-fluorophenyl)-N9,N9,10-trimethyl-11- Boxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2,9-dicarboxamide 060N-(3-chloro-4-fluorophenyl)-9-(hydroxymethyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 061N-(3-chloro-4-fluorophenyl)-9-(hydroxymethyl)-9,10- Adimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 0622-((3-chloro-4-fluorophenyl)carbamoyl)-9,10-dimethyl- D11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-9-carboxylic acid 063N-(3-chloro-4-fluorophenyl)-10-methyl-8- A(morpholinomethyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 064N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-8- B(piperidin-l-ylmethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 065N-(3-chloro-4-fluorophenyl)-8-((dimethylamino)methyl)- B10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 066N-(3-chloro-4-fluorophenyl)-8-((3,3-difluoropyrrolidin-1- Ayl)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 067N-(3-cyano-4-fluorophenyl)-8-((3,3-difluoropyrrolidin-1- Byl)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′-3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 0688-((3,3-difluoropyrrolidin-l-yl)methyl)-N-(4-fluoro-3- B(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 069N-(3-chloro-4-fluorophenyl)-10-methyl-11-oxo-8- A(pyrrolidin-1-ylmethyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 0708-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-10-methyl- A11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 071(R)-N-(2-bromo-5-chloro-4-fluorophenyl)-10-(2,2- Adifluoroethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 072(3R)-N-(3-chloro-4-fluorophenyl)-10-(2,2-difluoroethyl)- A3-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 073(R)-10-(2,2-difluoroethyl)-N-(4-fluoro-3- A(trifluoromethyl)phenyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 074(R)-N-(3-bromo-4-fluorophenyl)-10-(2,2-difluoroethyl)- A3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′.3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 075(R)-N-(2-bromo-3-fluoropyridin-4-yl)-10-(2,2- Adifluoroethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 076(R)-N-(3-cyano-4-fluorophenyl)-10-(2,2-difluoroethyl)-3- Amethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 077(R)-10-(2,2-difluoroethyl)-N-(4-fluoro-3-methylphenyl)- A3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 078(R)-N-(5-chloro-2,4-difluorophenyl)-10-(2,2- Bdifluoroethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide079_D1 (3R,8R*)-N-(3-chloro-4-fluorophenyl)-8-fluoro-3,8,10- Atrimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 079_D2(3R,8S*)-N-(3-chloro-4-fluorophenyl)-8-fluoro-3,8,10- Atrimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)- carboxamide 080_D1(3R,8S*)-N-(3-chloro-4-fluorophenyl)-3,8,10-trimethyl- A11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 080_D2(3R,8R*)-N-(3-chloro-4-fluorophenyl)-3,8,10-trimethyl- A11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 081_D1(3R,8S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 081_D2(3R,8R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 082_D1(3R,8S*)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 082_D2(3R,8R*)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-8- B(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 083_D1(3R,8S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 083_D2(3R,8R*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′.3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 084_D1(3R,8S*)-N-(3-bromo-2,4-difluorophenyl)-8- B(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 084_D2(3R,8R*)-N-(3-bromo-2,4-difluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 085_D1(3R,8S*)-N-(5-bromo-2,4-difluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 085_D2(3R,8R*)-N-(5-bromo-2,4-difluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 086_D1(3R,8S*)-N-(3-bromo-4-fluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 086_D2(3R,8R*)-N-(3-bromo-4-fluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 087_D1(3R,8S*)-N-(3-cyano-4-fluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 087_D2(3R,8R*)-N-(3-cyano-4-fluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 088_D1(3R,8S*)-N-(3-cyano-2,4-difluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 088_D2(3R,8R*)-N-(3-cyano-2,4-difluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 089_D1(3R,8S*)-N-(3-chloro-2,4-difluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 089_D2(3R,8R*)-N-(3-chloro-2,4-difluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 090_D1(3R,8S*)-N-(5-chloro-2,4-difluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 090_D2(3R,8R*)-N-(5-chloro-2,4-difluorophenyl)-8- A(hydroxymethyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5a]-[1,4]diazepine-2(7H)-carboxamide 091N-(3-chloro-4-fluorophenyl)-8-(2,2-difluoroethyl)-8- B(hydroxymethyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 092_D1(3R,8R*)-N-(3-chloro-4-fluorophenyl)-10-(2,2- Adifluoroethyl)-8-(hydroxymethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 092_D2(3R,8S*)-N-(3-chloro-4-fluorophenyl)-10-(2,2- Adifluoroethyl)-8-(hydroxymethyl)-3-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 0938-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)- B10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 094N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-8- B((methylamino)methyl)-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 0958-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-10-methyl- A11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 096_E1(R*)-N-(5-chloro-2,4-difluorophenyl)-8-((S*)-1- Ahydroxypropyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 096_E2(S*)-N-(5-chloro-2,4-difluorophenyl)-8-((R*)-1- Bhydroxypropyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 096_E3(S*)-N-(5-chloro-2,4-difluorophenyl)-8-((S*)-1- Bhydroxypropyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 096_E4(R*)-N-(5-chloro-2,4-difluorophenyl)-8-((R*)-1- Ahydroxypropyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 097_E1(R*)-N-(3-cyano-4-fluorophenyl)-8-((S*)-1- Ahydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 097_E2(S*)-N-(3-cyano-4-fluorophenyl)-8-((R*)-1- Bhydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 097_E3(S*)-N-(3-cyano-4-fluorophenyl)-8-((S*)-1- Bhydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 097_E4(R*)-N-(3-cyano-4-fluorophenyl)-8-((R*)-1- Ahydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 098_E1(R*)-N-(3-cyano-2,4-difluorophenyl)-8-((S*)-1- Ahydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 098_E2(S*)-N-(3-cyano-2,4-difluorophenyl)-8-((R*)-1- Chydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 098_E3(S*)-N-(3-cyano-2,4-difluorophenyl)-8-((S*)-1- Bhydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 098_E4(R*)-N-(3-cyano-2,4-difluorophenyl)-8-((R*)-1- Chydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 099_E1(R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((S*)-1- Ahydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 099_E2(5*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R*)-1- Bhydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 099_E3(S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((S*)-1- Ahydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 099_E4(R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R*)-1- Bhydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 100_E1N-(3-chloro-2,4-difluorophenyl)-8-(1-hydroxypropyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 101_E1N-(3-bromo-2,4-difluorophenyl)-8-(1-hydroxypropyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 102_E1N-(3-bromo-4-fluorophenyl)-8-(1-hydroxypropyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 103_E1N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8-(1- Ahydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 104_E18-(1-hydroxypropyl)-10-methyl-11-oxo-N-(3,4,5- Atrifluorophenyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 105_E18-(1-hydroxypropyl)-10-methyl-11-oxo-N-(2,3,4,5- Atetrafluorophenyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 106N-(3-chloro-4-fluorophenyl)-8-(1-hydroxybutyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 107_D1(3R,8S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)- A1-hydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 107_D2(3R,8R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)- A1-hydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 108_D1(3R,8S*)-N-(3-cyano-4-fluorophenyl)-8-((R)-1- Ahydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 108_D2(3R,8R*)-N-(3-cyano-4-fluorophenyl)-8-((R)-1- Bhydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 109_D1(3R,8S*)-N-(3-bromo-4-fluorophenyl)-8-((R)-1- Ahydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 109_D2(3R,8R*)-N-(3-bromo-4-fluorophenyl)-8-((R)-1- Ahydroxypropyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 110N-(3-chloro-4-fluorophenyl)-11-methyl-12-oxo- A3,4,7,8,9,10,11,12-octahydropyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazocine-2(1H)-carboxamide 111(Z)-N-(3-chloro-4-fluorophenyl)-11-methyl-12-oxo- A3,4,7,10,11,12-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazocine-2(1H)-carboxamide 112N-(3-cyano-4-fluorophenyl)-8-(3,3-difluoro-1- Ahydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 1132-((3-chloro-4-fluorophenyl)carbamoyl)-10-methyl-11- Doxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-7-carboxylic acid 114N-(3-chloro-4-fluorophenyl)-7-(hydroxymethyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 115N-(3-chloro-4-fluorophenyl)-8-(3-fluoro-1- Ahydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 116N-(3-chloro-4-fluorophenyl)-8-(3,3-difluoro-1- Ahydroxypropyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 1178-(acetamidomethyl)-N-(3-chloro-4-fluorophenyl)-10- Amethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 118N-(3-cyano-4-fluorophenyl)-8-(((2,2-difluoroethyl) Aamino)methyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 118_E1(R*)-N-(3-cyano-4-fluorophenyl)-8-(((2,2- Bdifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 118_E2(S*)-N-(3-cyano-4-fluorophenyl)-8-(((2,2- Adifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 1198-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- A(trifluoromethyl)phenyl)-10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 119_E1(R*)-8-((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- B(trifluoromethyl)phenyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 119_E2(S*)-8-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- A(trifluoromethyl)phenyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 120N-(3-cyano-4-fluorophenyl)-10-methyl-11-oxo-8-4(2,2,2- Atrifluoroethyl)amino)methyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 121N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-11- Aoxo-8-((2,2,2-trifluoroethyl)amino)methyl)-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 122_D1(3R,8S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)- A1-hydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 122_D2(3R,8R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-8-((R)- B1-hydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 123_D1(3R,8S*)-N-(3-cyano-4-fluorophenyl)-8-((R)-1- Ahydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 123_D2(3R,8R*)-N-(3-cyano-4-fluorophenyl)-8-((R)-1- Bhydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 124_D1(3R,8S*)-N-(3-bromo-4-fluorophenyl)-8-((R)-1- Ahydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 124_D2(3R,8R*)-N-(3-bromo-4-fluorophenyl)-8-((R)-1- Ahydroxyallyl)-3,10-dimethyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 125_E1(R*)-N-(5-bromo-2,4-difluorophenyl)-8-(((2,2- Bdifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 125_E2(S*)-N-(5-bromo-2,4-difluorophenyl)-8-(((2,2- Adifluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 126_E1(R*)-N-(5-chloro-2,4-difluorophenyl)-8-(((2,2- Bdifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 126_E2(S*)-N-(5-chloro-2,4-difluorophenyl)-8-(((2,2- Bdifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 127_E1(R*)-N-(3-cyano-2,4-difluorophenyl)-8-(((2,2- Cdifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 127_E2(S*)-N-(3-cyano-2,4-difluorophenyl)-8-(((2,2- Adifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 128_E1(R*)-N-(3-chloro-2,4-difluorophenyl)-8-(((2,2- Bdifluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 128_E2(S*)-N-(3-chloro-2,4-difluorophenyl)-8-(((2,2- Adifluoroethypamino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 129_E1(R*)-N-(3-bromo-2,4-difluorophenyl)-8-(((2,2- Bdifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 129_E2(S*)-N-(3-bromo-2,4-difluorophenyl)-84(2,2- Adifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 130_E1(R*)-N-(3-brorno-4-fluorophenyl)-8-(((2,2- Adifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 130_E2(S*)-N-(3-bromo-4-fluorophenyl)-8-(((2,2- Adifluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 131_E1(R*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8- B(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 131_E2(S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-8- B(((2,2-difluoroethyl)amino)methyl)-10-methyl-11-oxo-3,4,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2(7H)-carboxamide 132N-(3-chloro-4-fluorophenyl)-3-hydroxy-10′-methyl-11′- Aoxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide 133_D1 (3R,8R*)-8-fluoro-N-(4-fluoro-3- A(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 133_D2(3R,8S*)-8-fluoro-N-(4-fluoro-3- A(trifluoromethyl)phenyl)-8-(hydroxymethyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 134_D1(3R,8R)-N-(3-Cyano-4-fluorophenyl)-8-((2,2- Adifluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 134_D2(3R,8S)-N-(3-cyano-4-fluorophenyl)-8-((2,2- Adifluoroethoxy)methyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 135_D1(3R,8R)-8-(2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- A(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 135_D2(3R,8S)-8-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- A(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 136(R)-N-(3-cyano-4-fluorophenyl)-8,8-difluoro-3,10- Adimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide. 137_D1(3R,8R*)-N-(3-cyano-4-fluorophenyl)-8-fluoro-3,10- Adimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 137_D2(3R,8S*)-N-(3-Cyano-4-fluorophenyl)-8-fluoro-3,10- Adimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 138(3R,8R*)-8-fluoro-N-(4-fluoro-3- A(trifluoromethyl)phenyl)-3,10-dimethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 139(R)-N-(3-cyano-4-fluorophenyl)-3,8,8,10-tetramethyl-11- Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 140(R)-N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3,8,8,10- Atetramethyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 141(R)-N-(3-Cyano-4-fluorophenyl)-3-hydroxy-3′,10′- Bdimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide 142(R)-N-(3-Cyano-4-fluorophenyl)-3-fluoro-3′,10′- Adimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide 143(R)-N-(3-Cyano-4-fluorophenyl)-3,3-difluoro-3′,10′- Adimethyl-11′-oxo-1′,3′,4′,9′,10′,11′-hexahydro-2′H,7′H-spiro[cyclobutane-1,8′-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine]-2′-carboxamide 144_E1(S)-N-(3-Cyano-4-fluorophenyl)-8-fluoro-10-methyl-11- N/Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 144_E2(R)-N-(3-Cyano-4-fluorophenyl)-8-fluoro-10-methyl-11- N/Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 145_D1(R)-N-(3-Cyano-4-fluorophenyl)-8-(2,2-difluoroethoxy)- N/A10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 145_D2(S)-N-(3-Cyano-4-fluorophenyl)-8-(2,2-difluoroethoxy)- N/A10-methyl-11-oxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2- carboxamide 146(R)-N-(3-Cyano-4-fluorophenyl)-3-methyl-11-oxo- N/A1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 147(R)-N-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-methyl-11- N/Aoxo-1,3,4,7,8,9,10,11-octahydro-2H-pyrido[4′,3′:3,4]pyrazolo[1,5-a][1,4]diazepine-2-carboxamide 148(3R,8S)-N-(3-Cyano-4-fluorophenyl)-8-(hydroxymethyl)- N/A3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide 149(3R,8S)-N-(3-cyano-4-fluorophenyl)-8-(fluoromethyl)- A3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide 150(3R,8S)-N-(3-cyano-4-fluorophenyl)-8-((2,2- Adifluoroethoxy)methyl)-3,9-dimethyl-10-oxo-3,4,7,8,9,10-hexahydropyrido[4′,3′:3,4]pyrazolo[1,5-a]pyrazine-2(1H)-carboxamide

Example 3: Crystalline Form of Intermediate 16 Analogue

The crystalline form of compound 151, which is the di p-nitro-benzoicacid analogue of Intermediate 16, is described herein.

The X-ray crystal structure is shown in FIG. 1. Table 7 also showscrystal data and structure refinement for this intermediate.

TABLE 7 Crystal data and structure refinement. Empirical formula C27 H26N6 O8 Formula weight 562.54 Temperature 296(2)K Wavelength 1.54178 ACrystal system, space group Monoclinic, P 21 Unit cell dimensions a =13.87660(10) A alpha = 90 deg. b = 6.09990(10) A beta = 95.24 deg. c =15.60460(10) A gamma = 90 deg. Volume 1315.34(3) A{circumflex over ( )}3Z, Calculated density 2, 1.420 Mg/m{circumflex over ( )}3 Absorptioncoefficient 0.899 mm{circumflex over ( )}-1 F(000) 588 Crystal size 0.30× 0.30 × 0.15 mm Theta range for data collection 2.84 to 67.00 deg.Limiting indices −16 <= h <= 16, −6 <= k <= 6, −18 <= l <= 18Reflections collected/unique 11901/4328 [R(int) = 0.0202] Completenessto theta = 67.23 97.1% Absorption correction Semi-empirical fromequivalents Max. and min. transmission 0.7532 and 0.6289 Refinementmethod Full-matrix least-squares on F{circumflex over ( )}2Data/restraints/parameters 4328/1/371 Goodness-of-fit on F{circumflexover ( )}2 1.060 Final R indices [I > 2sigma(I)] R1 = 0.0288, wR2 =0.0778 R indices (all data) R1 = 0.0291, wR2 = 0.0781 Absolute structureparameter 0.07(15) Largest diff. peak and hole 0.162 and −0.124e.A{circumflex over ( )}-3

Table 8 also shows atomic coordinates (×10⁴) and equivalent isotropicdisplacement parameters (A²×10³) for the intermediate.

TABLE 8 Atomic coordinates and equivalent isotropic displacementparameters. x y z U(eq) O(1) 10223(1)  8815(2) 1656(1)  59(1) O(2) 6267(1) 12793(2) 1058(1)  48(1) O(3)  5071(1) 15033(3)  570(1)  81(1)O(4)  4223(2) 11263(7) 4829(2) 162(1) O(5)  3652(2) 14510(6) 4722(1)132(1) O(6)  9682(1)  8853(2) 4999(1)  56(1) O(7)  7319(1)  3348(3)8223(1)  83(1) O(8)  7495(1)  6700(3) 8642(1)  84(1) N(1)  7671(1) 8706(2) 1391(1)  39(1) N(2)  6991(1)  7802(2) 1845(1)  42(1) N(3) 8627(1)  6844(2) 4144(1)  36(1) N(4)  9298(1) 11581(3) 1053(1)  47(1)N(5)  4082(1) 12982(6) 4444(2) 105(1) N(6)  7554(1)  5251(3) 8112(1) 57(1) C(1)  7622(1) 11769(3)  313(1)  42(1) C(2)  7454(1)  9327(3) 486(1)  44(1) C(3)  7465(1)  7305(2) 2603(1)  39(1) C(4)  7014(1) 6415(3) 3363(1)  47(1) C(5)  7790(1)  5336(3) 3989(1)  40(1) C(6) 9150(1)  7438(3) 3399(1)  42(1) C(7)  8446(1)  7817(3) 2631(1)  37(1)C(8)  8558(1)  8748(3) 1841(1)  37(1) C(9)  9435(1)  9715(3) 1508(1) 43(1) C(10)  8374(1) 12757(3)  981(1)  45(1) C(11)  6694(1) 13079(3) 255(1)  46(1) C(12)  5452(1) 13897(3) 1126(1)  54(1) C(13)  5087(1)13564(3) 1990(1)  55(1) C(14)  4541(1) 15226(4) 2303(1)  70(1) C(15) 4221(1) 15041(5) 3113(2)  80(1) C(16)  4437(1) 13182(5) 3583(1)  78(1)C(17)  4965(1) 11492(5) 3278(2)  78(1) C(18)  5302(1) 11713(4) 2477(1) 65(1) C(19)  9008(1)  7555(2) 4917(1)  36(1) C(20)  8587(1)  6829(3)5730(1)  36(1) C(21)  8409(1)  4676(3) 5940(1)  43(1) C(22)  8072(1) 4170(3) 6720(1)  48(1) C(23)  7928(1)  5821(3) 7289(1)  43(1) C(24) 8137(1)  7966(3) 7120(1)  57(1) C(25)  8476(1)  8447(3) 6335(1)  54(1)C(26) 10114(1) 12629(4)  698(1)  67(1)

As can be seen, the stereo configuration of the Intermediate 16 analogueis 4S, 9R. Accordingly, the stereo configuration of compounds derivedfrom Intermediate 16 is known.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

1-32. (canceled)
 33. A compound of Formula III:

or a pharmaceutically acceptable salt thereof; wherein R¹ isC₁-C₆-alkyl; R² is, at each occurrence, independently selected from —OH,halo, C₁-C₆-alkyl, C₁-C₆-alkenyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂,C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl,C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸,C₀-C₆-alkyl-C(O)OR⁹, and C₀-C₆-alkyl-C(O)N(R)₂, wherein alkyl,cycloalkyl, and heterocycloalkyl are optionally substituted with 1 or 2groups, each independently selected from —OH and halo. R³ is, at eachoccurrence, independently selected from —OH, halo, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁴ is phenyl orpyridyl, wherein phenyl or pyridyl is optionally substituted with 1, 2,3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁵ isselected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁶ is selected from H,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, andC₀-C₆-alkyl-C₃-C₆-cycloalkyl; R⁷ is, at each occurrence, independentlyselected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C(O) C₁-C₆-alkyl andC₁-C₆-alkyl-OH; R⁸ is selected from H and C₁-C₆-alkyl; R⁹ is selectedfrom H and C₁-C₆-alkyl; R^(a) is, at each occurrence, independentlyselected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R^(b) is, at each occurrence,independently selected from H and C₁-C₆-alkyl; m is 0, 1, or 2; n is 0,1, or 2; and p is 0, 1, 2, 3, or
 4. 34. The compound of claim 33,wherein R¹ is —CH₃.
 35. The compound of claim 33, wherein at least oneR² is halo.
 36. The compound of claim 33, wherein at least one R² isC₀-C₆-alkyl-OR⁶.
 37. The compound of claim 33, wherein n is 0 or
 1. 38.The compound of claim 33, wherein at least one R³ is C₁-C₆-alkyl. 39.The compound of claim 33, wherein at least one R³ is —CH₃.
 40. Thecompound of claim 33, wherein R⁴ is phenyl or pyridyl, wherein phenyl orpyridyl is optionally substituted with 1, 2, 3, or 4 groups, eachindependently selected from halo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.41. The compound of claim 33, wherein R⁵ is H.
 42. The compound of claim33, wherein the compound of Formula III is selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 43. A pharmaceuticalcomposition comprising a compound of claim 33, and a pharmaceuticallyacceptable carrier.
 44. A method of treating an HBV infection in anindividual in need thereof, comprising administering to the individual atherapeutically effective amount of a compound of claim
 33. 45. A methodof inhibiting or reducing the formation or presence of HBVDNA-containing particles or HBV RNA-containing particles in anindividual, comprising administering to the individual a therapeuticallyeffective amount of a compound of claim
 33. 46. The method of claim 45,further comprising administering to the individual at least oneadditional therapeutic agent selected from the group consisting of anHBV polymerase inhibitor, immunomodulatory agents, interferon, viralentry inhibitor, viral maturation inhibitor, capsid assembly modulator,reverse transcriptase inhibitor, cyclophilin/TNF inhibitor, TLR-agonist,HBV vaccine, and any combination thereof.